Phenserine on the Alzheimer's Treatment Horizon, Study 1
NCT ID: NCT06774261
Last Updated: 2025-01-14
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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NOT_YET_RECRUITING
PHASE1
16 participants
INTERVENTIONAL
2025-02-01
2028-01-01
Brief Summary
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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.
Detailed Description
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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.
Study Population and Statistical Methods
A total of 16 participants are expected to be enrolled in this dose-ranging study. The primary population for analysis will be a modified intent-to-treat group, including all participants who received at least one dose of study medication and provided at least one follow-up exosome sample.
This study will provide critical data on the pharmacodynamic and pharmacokinetic profiles of phenserine, which will guide future research and potential therapeutic strategies for early to mild AD.
Background
In 2018, and in parallel with the conduct of the ELAD study that evaluated liraglutide (an established medication for Type 2 diabetes) for its neuroprotective effects in people with mild to moderate AD, we initiated a new selection process to identify additional drug candidates for re-purposing in AD, MCI and other forms of dementia. Drug repurposing, defined as "the application of established drug compounds to new therapeutic indications," offers a route to drug development that is accessible to academic institutions, government and research council programs, and charities and not-for-profit organizations, complementing the work of pharmaceutical and biotechnology companies. Repurposing an existing drug offers an attractive way of enhancing traditional drug development and accelerating new treatments for people with AD dementia and MCI into the clinic.
The international expert panel that participated in the 2018 assessment applied the same approach as in the earlier 2012 selection process. A total of five compounds or classes of compounds were nominated for further consideration by the panel. These compounds were ACE inhibitors, antiviral drugs, disease-modifying antirheumatic drugs (DMARDs), fasudil and phenserine. Following several rounds of prioritization, the panel came to a clear consensus that the three highest priority candidates for repurposing in AD, MCI and other dementias were phenserine, fasudil, and antiviral drugs. This protocol is designed to assess the safety and tolerability of phenserine compared to donepezil across a range of doses administered over a 8-week dosing period in participants with early or mild AD. The pharmacodynamic and pharmacokinetic activity of the two drugs will also be evaluated to determine dose-response relationships to identify an appropriate dose range for a subsequent Phase 2 study of phenserine.
Phenserine was initially developed as an acetylcholinesterase inhibitor (AChEI) , but there are several mechanisms by which phenserine may act on neuronal and synaptic loss , a key common pathway evident in AD. A range of pre-clinical studies indicate that phenserine suppresses interleukin-1b, reduces glutamate-induced excitotoxicity, protects against oxidative toxicity, reduces A-beta levels, improves neural precursor cell viability, elevates neurotrophic brain-derived neurotrophic factor, and inhibits amyloid-beta precursor protein synthesis. In the only published phase 2 randomized controlled trial (RCT), phenserine (10-15 mg b.i.d.) conferred improvement in cognition in people with AD receiving 12 weeks of the higher dose of phenserine. Safety and tolerability were very good. The proportion of withdrawals due to adverse events was 6% in the placebo arm and the highest dose groups, indicating that the optimal dose was probably not achieved for most patients. There were also methodological problems, prompting the authors to conclude that the full potential of phenserine for AD has not yet been fully evaluated.
The most common side-effects of phenserine are those associated with cholinesterase inhibition, i.e., nausea, vomiting and diarrhoea. The best predictor of cholinesterase linked gastrointestinal effects is the level of cholinesterase inhibition achieved, with the optimal therapeutic threshold being 50% inhibition. Given that the completed clinical trials with phenserine did not select patients based on biomarker confirmation of AD (meaning that a considerable proportion of participants likely did not have AD), and that the maximum dose did not lead to side-effects and thus many participants did not likely achieve a sufficiently high dose level, this study aims to evaluate the effects of an individualized maximum tolerated phenserine dose with adequate level of AChE inhibition to determine an appropriate dose range for subsequent efficacy trials.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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).
Phenserine
Phenserine is a next generation AChE inhibitor being developed for the treatment of AD. Unlike currently marketed AChE inhibitors, it has additional mechanisms of action that also include a mediating effect on cell death pathways and anti-amyloid activity, which may confer disease-modifying effects in people with AD.
Phenserine was originally identified and developed by the United States (U.S.) National Institute of Aging (NIA), part of the U.S National Institute of Health (NIH).
The study intervention will be open label. No blinding will be performed. Participants and site staff will, however, will be blinded to the results of the exosome and blood/CSF biomarker evaluations until the study is completed.
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.
Donepezil (Aricept®)
The substance donepezil (under the brand name Aricept®) is a resale product. No additional manufacturing or labeling measures is necessary for this study.
The NIMP, donepezil will be available in 5 mg and 10 mg strengths (table 3) and will be dispensed by the local pharmacy at the hospital where the participant in the donepezil arm is included. We have based the use of donepezil as a treatment in the study on the original product from Pfizer, but it is also possible to use generic products of donepezil if this is what the local pharmacy has for dispensing. Participants randomized to treatment with donepezil will follow the treatment plan according to the patient information leaflet. . These tablets are approved for clinical use and comply with all relevant safety and efficacy standards.
Interventions
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Phenserine
Phenserine is a next generation AChE inhibitor being developed for the treatment of AD. Unlike currently marketed AChE inhibitors, it has additional mechanisms of action that also include a mediating effect on cell death pathways and anti-amyloid activity, which may confer disease-modifying effects in people with AD.
Phenserine was originally identified and developed by the United States (U.S.) National Institute of Aging (NIA), part of the U.S National Institute of Health (NIH).
The study intervention will be open label. No blinding will be performed. Participants and site staff will, however, will be blinded to the results of the exosome and blood/CSF biomarker evaluations until the study is completed.
Donepezil (Aricept®)
The substance donepezil (under the brand name Aricept®) is a resale product. No additional manufacturing or labeling measures is necessary for this study.
The NIMP, donepezil will be available in 5 mg and 10 mg strengths (table 3) and will be dispensed by the local pharmacy at the hospital where the participant in the donepezil arm is included. We have based the use of donepezil as a treatment in the study on the original product from Pfizer, but it is also possible to use generic products of donepezil if this is what the local pharmacy has for dispensing. Participants randomized to treatment with donepezil will follow the treatment plan according to the patient information leaflet. . These tablets are approved for clinical use and comply with all relevant safety and efficacy standards.
Eligibility Criteria
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Inclusion Criteria
* 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 1.0.
* 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..
Exclusion Criteria
* 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.
50 Years
ALL
No
Sponsors
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Helse Fonna
OTHER
St. Olavs Hospital
OTHER
University Hospital of North Norway
OTHER
University of Exeter
OTHER
National Institutes of Health (NIH)
NIH
Helse Stavanger HF
OTHER_GOV
Responsible Party
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Central Contacts
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References
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Reijs BL, Teunissen CE, Goncharenko N, Betsou F, Blennow K, Baldeiras I, Brosseron F, Cavedo E, Fladby T, Froelich L, Gabryelewicz T, Gurvit H, Kapaki E, Koson P, Kulic L, Lehmann S, Lewczuk P, Lleo A, Maetzler W, de Mendonca A, Miller AM, Molinuevo JL, Mollenhauer B, Parnetti L, Rot U, Schneider A, Simonsen AH, Tagliavini F, Tsolaki M, Verbeek MM, Verhey FR, Zboch M, Winblad B, Scheltens P, Zetterberg H, Visser PJ. The Central Biobank and Virtual Biobank of BIOMARKAPD: A Resource for Studies on Neurodegenerative Diseases. Front Neurol. 2015 Oct 15;6:216. doi: 10.3389/fneur.2015.00216. eCollection 2015.
Tweedie D, Fukui K, Li Y, Yu QS, Barak S, Tamargo IA, Rubovitch V, Holloway HW, Lehrmann E, Wood WH 3rd, Zhang Y, Becker KG, Perez E, Van Praag H, Luo Y, Hoffer BJ, Becker RE, Pick CG, Greig NH. Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms. PLoS One. 2016 Jun 2;11(6):e0156493. doi: 10.1371/journal.pone.0156493. eCollection 2016.
Greig NH, De Micheli E, Holloway HW, Yu QS, Utsuki T, Perry TA, Brossi A, Ingram DK, Deutsch J, Lahiri DK, Soncrant TT. The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamics. Acta Neurol Scand Suppl. 2000;176:74-84. doi: 10.1034/j.1600-0404.2000.00311.x.
Chang CF, Lai JH, Wu JC, Greig NH, Becker RE, Luo Y, Chen YH, Kang SJ, Chiang YH, Chen KY. (-)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury. Brain Res. 2017 Dec 15;1677:118-128. doi: 10.1016/j.brainres.2017.09.015. Epub 2017 Sep 27.
Becker RE, Greig NH, Giacobini E, Schneider LS, Ferrucci L. A new roadmap for drug development for Alzheimer's disease. Nat Rev Drug Discov. 2014 Feb;13(2):156. doi: 10.1038/nrd3842-c2. Epub 2013 Dec 20. No abstract available.
Braida D, Sala M. Eptastigmine: ten years of pharmacology, toxicology, pharmacokinetic, and clinical studies. CNS Drug Rev. 2001 Winter;7(4):369-86. doi: 10.1111/j.1527-3458.2001.tb00205.x.
Desai A, Grossberg G. Review of rivastigmine and its clinical applications in Alzheimer's disease and related disorders. Expert Opin Pharmacother. 2001 Apr;2(4):653-66. doi: 10.1517/14656566.2.4.653.
Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging. 2004;21(7):453-78. doi: 10.2165/00002512-200421070-00004.
Nordberg A, Kadir A, Andreasen N, Almkvist O, Wall A, Langstrom B, Zetterberg H. Correlations between Alzheimer's Disease Cerebrospinal Fluid Biomarkers and Cerebral Glucose Metabolism after 12 Months of Phenserine Treatment. J Alzheimers Dis. 2015;47(3):691-704. doi: 10.3233/JAD-132474.
Kadir A, Andreasen N, Almkvist O, Wall A, Forsberg A, Engler H, Hagman G, Larksater M, Winblad B, Zetterberg H, Blennow K, Langstrom B, Nordberg A. Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease. Ann Neurol. 2008 May;63(5):621-31. doi: 10.1002/ana.21345.
Becker RE, Greig NH, Lahiri DK, Bledsoe J, Majercik S, Ballard C, Aarsland D, Schneider LS, Flanagan D, Govindarajan R, Sano M, Ferrucci L, Kapogiannis D. (-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer's Disease. Curr Alzheimer Res. 2018;15(9):883-891. doi: 10.2174/1567205015666180110120026.
Greig NH, Ruckle J, Comer P, Brownell L, Holloway HW, Flanagan DR Jr, Canfield CJ, Burford RG. Anticholinesterase and pharmacokinetic profile of phenserine in healthy elderly human subjects. Curr Alzheimer Res. 2005 Oct;2(4):483-92. doi: 10.2174/156720505774330564.
Other Identifiers
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EuCT: 2023-510282-10-00
Identifier Type: -
Identifier Source: org_study_id