Clinical trial NCT06362707: Fasudil Trial for Treatment of Early Alzheimer's Disease (FEAD)
Official title: A Placebo Controlled Randomized Double-blind Parallel Group 12-month Trial of Fasudil for the Treatment of Early Alzheimer's Disease (FEAD)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cognitive Decline, Mild
Alzheimer Disease
Keywords: Alzheimer Disease
Mild Cognitive Decline
Fasudil
Lead sponsor: Helse Stavanger HF
Sponsor class: OTHER_GOV
Collaborators: name: University of Exeter
name: Helse Fonna
name: St. Olavs Hospital
name: University Hospital, Akershus
name: Haraldsplass Deaconess Hospital
First posted: 2024-04-12
Enrollment: 200
Sex: ALL
Minimum age (years): 50
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The goal of this placebo-controlled double-blind Phase 2 clinical trial is to test in people with early Alzheimer's Disease.

The main questions it aims to answer are:

* Does treatment with fasudil, a ROCK-inhibitor, lead to significant improvement in working memory (based on computer-based working memory composite scores) compared to placebo in individuals with early Alzheimer's disease (AD) over 12 months?
* What is the effect of fasudil treatment for 12 months on other cognitive functions, brain metabolism measured by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), and other relevant clinical functions and biomarkers in individuals with early Alzheimer's disease (AD)?
* Treatment will be escalated to a maintenance dose of 120 mg total daily dose for up to 50 weeks, with regular clinic visits for efficacy and safety evaluations.
* Assessments will include cognitive tests, FDG-PET scans, and biomarker analyses, with follow-up by the Data and Safety Monitoring Board for ongoing safety review.

The study will compare participants receiving fasudil with those receiving placebo to see if fasudil treatment leads to improvements in cognitive functions, brain metabolism measured by FDG-PET.

Detailed description: This is a 2-arm, parallel-group, 12-month, randomized, placebo-controlled double-blind Phase 2 trial of fasudil in up to 200 people with early AD. Fasudil is a ROCK-inhibitor (rho-associated protein kinase inhibitor), a vasodilator that is approved for treating vasospasms following subarachnoidal bleeding in Japan and China. The drug has acceptable safety and tolerability and has been shown to protect neurons and synapses in animal models of AD. Eligible participants must have Stage 3-4 mild cognitive impairment (MCI) or mild dementia due to AD, as recently defined by FDA Guidance, and have shown a significant change on a validated AD biomarker (e.g. amyloid PET scans or CSF Aβ 1-42 or blood p-tau 217 levels). In addition, they must have a CDR Global rating of 0.5 or 1.0 and an MRI scan within the past two years that has no findings inconsistent with AD.

People who meet all inclusion criteria will be enrolled in three successive cohorts of 20, 50, and 130 people, respectively. Participants will be randomized 1:1 to receive fasudil or a matching placebo. All participants will undergo a 2-week titration period at a total daily dose of 60 mg (20 mg tds) before being escalated to the maintenance dose of 120 mg total daily dose (40 mg tds) for up to 50 additional weeks of treatment. The selected dose of 120 mg per day is optimized for potential efficacy over the planned 12-month treatment while providing a reasonable margin of safety based on available clinical and nonclinical data. Participants will visit the clinic for efficacy and/or safety evaluations at 2-week intervals for the first month and then monthly thereafter (see Table 1. Schedule of Assessments).

The Data and Safety Monitoring Board (DSMB) will perform an unblinded review of the safety and pharmacokinetic (PK) data once all ongoing patients in Cohort 1 have completed at least 3 months of treatment and make recommendations to the study team that may include stopping or continuing the study (with or without changes to the study procedures).

The DSMB will continue to review all data available from Cohorts 1-3 for the remainder of the study at 3-monthly intervals, or more frequently if warranted by emergent data, and recommend any changes to the study procedures to ensure appropriate safety oversight and management of study participants through completion of the study.

The primary efficacy outcome is the FLAME (Factors of Longitudinal Attention, Memory and Executive Function) computer-based working memory composite. The key secondary outcomes are based on the expression of the AD-like hypometabolic pattern on FDG-PET and additional cognitive tests from the FLAME battery, including memory, working memory, attention, and executive functions. Additional secondary outcomes include CSF and blood-based AD biomarkers, and clinical measures including Clinical Global Impression of Change (CGIC), and Clinical Dementia Rating (CDR), neuropsychiatric symptoms (NPI), instrumental activities of daily living (Amsterdam IADL scale) and quality of life (DEMQOL). Standard safety measures include monthly assessments of adverse events (AEs), vital signs, and laboratory tests (including blood and urine analyses) as well as ECGs and the Columbia-Suicide Severity Rating Scale (C-SSRS).

Eligibility criteria: Inclusion Criteria:

* Early AD, eg Stage 3 MCI or Stage 4 (mild AD dementia), as recently defined by the FDA (2018; Figure 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 levels or blood p-tau 217 cut-offs as determined by the clinical research laboratory)
* A CDR Global rating of 0.5 or 1.0 (Morris 1993) and have an MRI scan within the past two years that has no findings inconsistent with AD
* Capacity to give informed consent based on the clinical judgement of an experienced clinician
* The participant needs to have a reliable study partner with regular contact (a combination of face-to-face visits and telephone contact is acceptable) who has sufficient interaction with the participant to provide meaningful input into rating scales
* Age from 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 within 14 days of baseline assessments and agree to the use of effective birth control throughout their participation in the study

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 (Fazekas et al 1987).
* A history of cerebrovascular bleeding or severe bleeding of the digestive tract, lungs, nose or skin
* Severe renal impairment (GFR \<30) or serum creatinine or urea nitrogen values ≥3 times Upper normal limit (ULN) at screening or baseline
* Moderate to severe hepatic impairment. Serum alanine transaminase (ALT) or aspartate transaminase levels ≥3 times ULN at screening or baseline
* Currently poorly controlled diabetes as indicated by HbA1c values \>9
* White blood cell (WBC) values \<3.5 K/μl
* History of paralytic ileus or current severe chronic constipation
* Known allergy to fasudil or established systemic inflammatory disease or autoimmune disease.
* Clinically significant hypotension defined by blood pressure values \<90/60 mmHg, regardless of the individual's sitting or standing position and associated with relevant clinical symptoms (e.g., tachycardia, dizziness, syncope)
* Current clinically significant depression or other mental disorder likely to affect cognition or interfere with study participation
* Recent (within 3 months) relevant medication changes. Participants must have been on stable anti-dementia (cholinesterase inhibitors or memantine) or anti-depressive medications for at least three months before the study
* 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 stability on them for a minimum of 3 months prior to the start of the study
* Participation in other drug trials
* Currently ongoing life-threatening disease, such as metastatic cancer, advanced cardiovascular disease, advanced respiratory disease, terminal kidney disease, or advanced stages of infectious diseases
* Any current or past neurological disease unrelated to Alzheimer's disease with cognitive sequelae
* A Corrected QT (QTc) interval ≥ 460 milliseconds for males or ≥ 470 milliseconds for females will be considered abnormal during the ECG assessments

Primary outcomes:
measure: Cognition
timeFrame: The cognitive battery will be performed at baseline and every three months until last visit, supported by trial staff (up to 1 year).
measure: Brain metabolism
timeFrame: The outcome will be change in FDG-PET between baseline and at 12 months.
Secondary outcomes:
measure: Plasma levels of ptau217
timeFrame: Collection of blood samples will occur at baseline and the 12-month visit.
measure: Plasma levels of nfl
timeFrame: Collection of blood samples will occur at baseline and the 12-month visit.
measure: Levels of cerebrospinal Aβ1-40 and Aβ1-42
timeFrame: Collection of CSF samples will occur at baseline and the 12-month visit.
measure: Levels of cerebrospinal tau and p-tau
timeFrame: Collection of CSF samples will occur at baseline and the 12-month visit.
measure: Blood pressure (Safety assessments)
timeFrame: Conducted at all visits throughout the 12-month duration of the study. Additionally, the Columbia Suicide Severity Rating Scale (C-SSRS) will be administered at screening, month 6, and month 12
measure: Pulse (Safety assessments)
timeFrame: Conducted at all visits throughout the 12-month duration of the study.
measure: Urine testing (Safety assessments)
timeFrame: Conducted at baseline and all visits throughout the 12-month duration of the study.
measure: Blood urea nitrogen (BUN) (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Potassium (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Sodium (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Calcium (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Glucose (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Hemoglobin (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Creatinine (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Total and direct bilirubin (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: CRP (C-reactive protein) (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Aspartate aminotransferase (AST) (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Serum glutamic-oxaloacetic transaminase (SGOT) (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Alanine aminotransferase (ALT) (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Serum glutamic-pyruvic transaminase (SGPT) (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Alkaline phosphatase (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study.
measure: Electrocardiogram (ECG) (Safety assessments)
timeFrame: Conducted at baseline and all monthly visits throughout the 12-month duration of the study. Additionally, the Columbia Suicide Severity Rating Scale (C-SSRS) will be administered at screening, month 6, and month 12
measure: Columbia Suicide Severity Rating Scale (C-SSRS) (Safety assessments)
timeFrame: Screening visit, month 6 and 12 months visits
Other outcomes:
Locations:
city: Tromsø
country: Norway
facility: University Hospital of North Norway
state: Nordland
city: Haugesund
country: Norway
facility: Haugesund Hospital
state: Rogaland
city: Stavanger
country: Norway
facility: Stavanger University Hospital
state: Rogaland
city: Trondheim
country: Norway
facility: St. Olavs Hospital:
state: Trøndelag
city: Bergen
country: Norway
facility: Haraldsplass Deaconess Hospital
state: Vestland
city: Oslo
country: Norway
facility: Akershus Hospital:
Study officials:
References:
citation: Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, Takayasu M, Hidaka H. Mechanism of action of a novel antivasospasm drug, HA1077. J Pharmacol Exp Ther. 1987 Jun;241(3):1033-40.
citation: Atri A, Frolich L, Ballard C, Tariot PN, Molinuevo JL, Boneva N, Windfeld K, Raket LL, Cummings JL. Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials. JAMA. 2018 Jan 9;319(2):130-142. doi: 10.1001/jama.2017.20373.
citation: Ballard C, Atri A, Boneva N, Cummings JL, Frolich L, Molinuevo JL, Tariot PN, Raket LL. Enrichment factors for clinical trials in mild-to-moderate Alzheimer's disease. Alzheimers Dement (N Y). 2019 May 20;5:164-174. doi: 10.1016/j.trci.2019.04.001. eCollection 2019.
citation: Ballard C, Aarsland D, Cummings J, O'Brien J, Mills R, Molinuevo JL, Fladby T, Williams G, Doherty P, Corbett A, Sultana J. Drug repositioning and repurposing for Alzheimer disease. Nat Rev Neurol. 2020 Dec;16(12):661-673. doi: 10.1038/s41582-020-0397-4. Epub 2020 Sep 16.
citation: Brooker H, Williams G, Hampshire A, Corbett A, Aarsland D, Cummings J, Molinuevo JL, Atri A, Ismail Z, Creese B, Fladby T, Thim-Hansen C, Wesnes K, Ballard C. FLAME: A computerized neuropsychological composite for trials in early dementia. Alzheimers Dement (Amst). 2020 Oct 14;12(1):e12098. doi: 10.1002/dad2.12098. eCollection 2020.
citation: Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB, Edison P, Hagan JJ, Holmes C, Jones E, Katona C, Kearns I, Kehoe P, Mudher A, Passmore A, Shepherd N, Walsh F, Ballard C. Drug repositioning for Alzheimer's disease. Nat Rev Drug Discov. 2012 Nov;11(11):833-46. doi: 10.1038/nrd3869.
citation: Couch BA, DeMarco GJ, Gourley SL, Koleske AJ. Increased dendrite branching in AbetaPP/PS1 mice and elongation of dendrite arbors by fasudil administration. J Alzheimers Dis. 2010;20(4):1003-8. doi: 10.3233/JAD-2010-091114.
citation: Corbett A, Owen A, Hampshire A, Grahn J, Stenton R, Dajani S, Burns A, Howard R, Williams N, Williams G, Ballard C. The Effect of an Online Cognitive Training Package in Healthy Older Adults: An Online Randomized Controlled Trial. J Am Med Dir Assoc. 2015 Nov 1;16(11):990-7. doi: 10.1016/j.jamda.2015.06.014.
citation: Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994 Dec;44(12):2308-14. doi: 10.1212/wnl.44.12.2308.
citation: Elliott C, Rojo AI, Ribe E, Broadstock M, Xia W, Morin P, Semenov M, Baillie G, Cuadrado A, Al-Shawi R, Ballard CG, Simons P, Killick R. A role for APP in Wnt signalling links synapse loss with beta-amyloid production. Transl Psychiatry. 2018 Sep 20;8(1):179. doi: 10.1038/s41398-018-0231-6.
citation: Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol. 1987 Aug;149(2):351-6. doi: 10.2214/ajr.149.2.351.
citation: Fukumoto Y, Yamada N, Matsubara H, Mizoguchi M, Uchino K, Yao A, Kihara Y, Kawano M, Watanabe H, Takeda Y, Adachi T, Osanai S, Tanabe N, Inoue T, Kubo A, Ota Y, Fukuda K, Nakano T, Shimokawa H. Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ J. 2013;77(10):2619-25. doi: 10.1253/circj.cj-13-0443. Epub 2013 Aug 3.
citation: Herholz K, Salmon E, Perani D, Baron JC, Holthoff V, Frolich L, Schonknecht P, Ito K, Mielke R, Kalbe E, Zundorf G, Delbeuck X, Pelati O, Anchisi D, Fazio F, Kerrouche N, Desgranges B, Eustache F, Beuthien-Baumann B, Menzel C, Schroder J, Kato T, Arahata Y, Henze M, Heiss WD. Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage. 2002 Sep;17(1):302-16. doi: 10.1006/nimg.2002.1208.
citation: Hinderling PH, Karara AH, Tao B, Pawula M, Wilding I, Lu M. Systemic availability of the active metabolite hydroxy-fasudil after administration of fasudil to different sites of the human gastrointestinal tract. J Clin Pharmacol. 2007 Jan;47(1):19-25. doi: 10.1177/0091270006293767.
citation: Ido K, Kurogi R, Kurogi A, Nishimura K, Arimura K, Nishimura A, Ren N, Kada A, Matsuo R, Onozuka D, Hagihara A, Takagishi S, Yamagami K, Takegami M, Nohara Y, Nakashima N, Kamouchi M, Date I, Kitazono T, Iihara K; J-ASPECT Study Collaborators. Effect of treatment modality and cerebral vasospasm agent on patient outcomes after aneurysmal subarachnoid hemorrhage in the elderly aged 75 years and older. PLoS One. 2020 Apr 9;15(4):e0230953. doi: 10.1371/journal.pone.0230953. eCollection 2020.
citation: Gillett R. Assessment of working memory performance in self-ordered selection tests. Cortex. 2007 Nov;43(8):1047-56. doi: 10.1016/s0010-9452(08)70702-0.
citation: Grill JD, Di L, Lu PH, Lee C, Ringman J, Apostolova LG, Chow N, Kohannim O, Cummings JL, Thompson PM, Elashoff D; Alzheimer's Disease Neuroimaging Initiative. Estimating sample sizes for predementia Alzheimer's trials based on the Alzheimer's Disease Neuroimaging Initiative. Neurobiol Aging. 2013 Jan;34(1):62-72. doi: 10.1016/j.neurobiolaging.2012.03.006. Epub 2012 Apr 13.
citation: Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA. Peripheral delivery of a ROCK inhibitor improves learning and working memory. Behav Neurosci. 2009 Feb;123(1):218-23. doi: 10.1037/a0014260.
citation: Huntley J, Corbett A, Wesnes K, Brooker H, Stenton R, Hampshire A, Ballard C. Online assessment of risk factors for dementia and cognitive function in healthy adults. Int J Geriatr Psychiatry. 2018 Feb;33(2):e286-e293. doi: 10.1002/gps.4790. Epub 2017 Sep 27.
citation: Ismail Z, Smith EE, Geda Y, Sultzer D, Brodaty H, Smith G, Aguera-Ortiz L, Sweet R, Miller D, Lyketsos CG; ISTAART Neuropsychiatric Symptoms Professional Interest Area. Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment. Alzheimers Dement. 2016 Feb;12(2):195-202. doi: 10.1016/j.jalz.2015.05.017. Epub 2015 Jun 18.
citation: Janelidze S, Palmqvist S, Leuzy A, Stomrud E, Verberk IMW, Zetterberg H, Ashton NJ, Pesini P, Sarasa L, Allue JA, Teunissen CE, Dage JL, Blennow K, Mattsson-Carlgren N, Hansson O. Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma Abeta42/Abeta40 and p-tau. Alzheimers Dement. 2022 Feb;18(2):283-293. doi: 10.1002/alz.12395. Epub 2021 Jun 20.
citation: Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, Lopez OL, DeKosky ST. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci. 2000 Spring;12(2):233-9. doi: 10.1176/jnp.12.2.233.
citation: Kamei S, Oishi M, Takasu T. Evaluation of fasudil hydrochloride treatment for wandering symptoms in cerebrovascular dementia with 31P-magnetic resonance spectroscopy and Xe-computed tomography. Clin Neuropharmacol. 1996 Oct;19(5):428-38. doi: 10.1097/00002826-199619050-00006.
citation: Killick R, Ribe EM, Al-Shawi R, Malik B, Hooper C, Fernandes C, Dobson R, Nolan PM, Lourdusamy A, Furney S, Lin K, Breen G, Wroe R, To AW, Leroy K, Causevic M, Usardi A, Robinson M, Noble W, Williamson R, Lunnon K, Kellie S, Reynolds CH, Bazenet C, Hodges A, Brion JP, Stephenson J, Simons JP, Lovestone S. Clusterin regulates beta-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Mol Psychiatry. 2014 Jan;19(1):88-98. doi: 10.1038/mp.2012.163. Epub 2012 Nov 20.
citation: Koster N, Knol DL, Uitdehaag BM, Scheltens P, Sikkes SA. The sensitivity to change over time of the Amsterdam IADL Questionnaire((c)). Alzheimers Dement. 2015 Oct;11(10):1231-40. doi: 10.1016/j.jalz.2014.10.006. Epub 2015 Jan 15.
citation: Landau SM, Harvey D, Madison CM, Koeppe RA, Reiman EM, Foster NL, Weiner MW, Jagust WJ; Alzheimer's Disease Neuroimaging Initiative. Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol Aging. 2011 Jul;32(7):1207-18. doi: 10.1016/j.neurobiolaging.2009.07.002. Epub 2009 Aug 5.
citation: Morbelli S, Brugnolo A, Bossert I, Buschiazzo A, Frisoni GB, Galluzzi S, van Berckel BN, Ossenkoppele R, Perneczky R, Drzezga A, Didic M, Guedj E, Sambuceti G, Bottoni G, Arnaldi D, Picco A, De Carli F, Pagani M, Nobili F. Visual versus semi-quantitative analysis of 18F-FDG-PET in amnestic MCI: an European Alzheimer's Disease Consortium (EADC) project. J Alzheimers Dis. 2015;44(3):815-26. doi: 10.3233/JAD-142229.
citation: Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412-4. doi: 10.1212/wnl.43.11.2412-a. No abstract available.
citation: Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016 Mar;7(2):27-31. doi: 10.4103/0976-0105.177703.
citation: 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.
citation: Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984 Nov;141(11):1356-64. doi: 10.1176/ajp.141.11.1356.
citation: Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, Schmitt FA, Grundman M, Thomas RG, Ferris SH. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S22-32. doi: 10.1097/00002093-199700112-00004.
citation: Sellers KJ, Elliott C, Jackson J, Ghosh A, Ribe E, Rojo AI, Jarosz-Griffiths HH, Watson IA, Xia W, Semenov M, Morin P, Hooper NM, Porter R, Preston J, Al-Shawi R, Baillie G, Lovestone S, Cuadrado A, Harte M, Simons P, Srivastava DP, Killick R. Amyloid beta synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. Alzheimers Dement. 2018 Mar;14(3):306-317. doi: 10.1016/j.jalz.2017.09.008. Epub 2017 Oct 19.
citation: Smith SC, Lamping DL, Banerjee S, Harwood RH, Foley B, Smith P, Cook JC, Murray J, Prince M, Levin E, Mann A, Knapp M. Development of a new measure of health-related quality of life for people with dementia: DEMQOL. Psychol Med. 2007 May;37(5):737-46. doi: 10.1017/S0033291706009469. Epub 2006 Dec 19.
citation: Song Y, Chen X, Wang LY, Gao W, Zhu MJ. Rho kinase inhibitor fasudil protects against beta-amyloid-induced hippocampal neurodegeneration in rats. CNS Neurosci Ther. 2013 Aug;19(8):603-10. doi: 10.1111/cns.12116. Epub 2013 May 3.
citation: Suzuki Y, Shibuya M, Satoh S, Sugiyama H, Seto M, Takakura K. Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study. Neurol Med Chir (Tokyo). 2008 Jun;48(6):241-7; discussion 247-8. doi: 10.2176/nmc.48.241.
citation: Tanaka K, Minami H, Kota M, Kuwamura K, Kohmura E. Treatment of cerebral vasospasm with intra-arterial fasudil hydrochloride. Neurosurgery. 2005 Feb;56(2):214-23; discussion 214-23. doi: 10.1227/01.neu.0000147975.24556.bc.
citation: van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. doi: 10.1056/NEJMoa2212948. Epub 2022 Nov 29.
citation: Wesnes KA, Brooker H, Ballard C, McCambridge L, Stenton R, Corbett A. Utility, reliability, sensitivity and validity of an online test system designed to monitor changes in cognitive function in clinical trials. Int J Geriatr Psychiatry. 2017 Dec;32(12):e83-e92. doi: 10.1002/gps.4659. Epub 2017 Jan 27.
citation: Williams MM, Storandt M, Roe CM, Morris JC. Progression of Alzheimer's disease as measured by Clinical Dementia Rating Sum of Boxes scores. Alzheimers Dement. 2013 Feb;9(1 Suppl):S39-44. doi: 10.1016/j.jalz.2012.01.005. Epub 2012 Aug 1.