Clinical trial NCT02098824: Symptomatic Treatment of Vascular Cognitive Impairment
Official title: Symptomatic Treatment of Vascular Cognitive Impairment
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Mild Cognitive Impairment (Vascular)
Mild Cognitive Disorder (Vascular)
Vascular Dementia
Keywords: vascular cognitive impairment
treatment
cerebrovascular lesions
memory impairment
executive dysfunction
neuronal networks
white matter tracts
monoaminergic systems
cholinergic systems
DTI
rs-fMRI
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2014-03-28
Enrollment: 30
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief summary: Single center threeway double blind cross over trial investigating the pharmacological responsivity in patients with VCI using a challenge aimed at the monoaminergic and cholinergic neuronal systems

Detailed description: Vascular Cognitive Impairment is an important cause of cognitive impairment and dementia. Till now, there are no approved symptomatic treatments for Vascular Cognitive Impairment. Research on novel pharmacological treatments that may reduce clinical symptoms in these patients is needed. Evidence suggests that executive dysfunction and memory impairment in Vascular Cognitive Impairment are caused by damage to monoaminergic and cholinergic neurotransmitter-systems, respectively.

However, patients with Vascular Cognitive Impairment form a clinically heterogeneous group, i.e. the extent to which executive function and memory are affected differs from patient to patient. Previous intervention studies have not taken this inter-patient variability into account. Individually tailored pharmacological interventions, aimed at the affected neurotransmitter systems, may ameliorate cognitive symptoms in patients with Vascular Cognitive Impairment. Using a pharmacological challenge, it is possible to detect individual sensitivity to specific pharmacological interventions. Furthermore, with the use of novel MRI techniques, it is possible to correlate the location and severity of cerebrovascular lesions to impaired structural and functional connectivity in each subject.

The investigators will recruit 30 patients with Vascular Cognitive Impairment (according to the criteria of the American Heart Association/American Stroke Association), at the Alzheimer Center of the VU University Medical Center and the Utrecht University Medical Center. They will also undergo MRI, including diffusion tensor imaging MRI (DTI)/'fiber tracking'; and resting state (RS) functional MRI (fMRI). In a double-blind, three-way, case cross over trial, the investigators will study the effects of methylphenidate on executive function and of galantamine on episodic memory function. During three separate visits, patients will receive the pharmacological interventions (placebo, methylphenidate, and galantamine) at the investigators Clinical Research Unit. Also, during a study day the investigators will collect blood samples at different timepoints.

Eligibility criteria: Inclusion Criteria:

* Outpatients
* Objective executive dysfunction and/or memory impairment on neuropsychological tests and imaging evidence of cerebrovascular disease (white matter changes (Fazekas ≥2, (lacunar) infarcts)
* Mini Mental State Examination (MMSE) ≥16
* Clinical Dementia Rating Score (CDR of 0.5-1)
* No contraindication for treatment with a Cholinesterase inhibitor (CEI) or Methylphenidate (MPH) (www.fk.cvz.nl)
* Assessed by the treating neurologist as mentally capable of understanding the implications of study participation
* Presence of an informant/caregiver at the information visit, signing of informed consent, and all study visits

Exclusion Criteria:

* Clinically relevant history of abnormal physical or mental health interfering with the study as determined by medical history taking and physical examinations obtained during the screening visit and/or at the study day as judged by the investigator;
* Clinically relevant abnormal laboratory results, electrocardiogram (ECG) and vital signs, or physical findings at screening and/or at the start of the study day (as judged by the investigator);
* Unwilling to or unable to stop smoking on the study day until the end of the study day
* Other causes that can explain cognitive symptoms including but not limited to: delirium, multiple sclerosis, amyotrophic lateral sclerosis, progressive supranuclear palsy, mental retardation, infectious encephalitis that led to persistent cognitive deficits or head trauma with loss of consciousness that led to persistent cognitive deficits
* Use of neuroleptics
* Use of celiprolol or sotalol
* Use of MAO-A/B inhibitors
* Current use of centrally acting anticholinergics (e.g. oxybutynin, mebeverine, ipratropium(bromide))
* Use of benzodiazepine within 48 hours before a study day
* Current use of a CEI (rivastigmine, galantamine, donepezil)
* Alcohol abuse (defined as use of alcohol despite significant areas of dysfunction, evidence of physical dependence, and/or related hardship due to alcohol)
* Use of recreational drugs
* Concomitant use of inhibitors of CYP2D6 (a/o kinidine, paroxetine, fluoxetine) or of CYP3A4 (a/o ketoconazole, ritonavir); unless patients are on a stable dose without any recent or upcoming changes
* Any other condition that in the opinion of the investigator would complicate or compromise the study, or the well being of the subject.
* Any contra-indication for MRI

Primary outcomes:
measure: Change on performance on executive function and on memory after active challenge
timeFrame: timepoints 1 hour, 2.5 hours and 3.5 hours
Secondary outcomes:
measure: Change on performance on other Neurocart tests after active challenge
timeFrame: Timepoints 1.0 hour, 2.5 hours and 3.5 hours
Other outcomes:
measure: Locations and number of cerebrovascular lesions
timeFrame: Single MRI scan after screening
measure: Structural connectivity of white matter tracts
timeFrame: Single MRI after screening
measure: Functional connectivity in resting state networks
timeFrame: Single MRI, after screening
measure: Maximum concentration (Cmax)
timeFrame: t-1.5, t=1, t=2.5, t=3.5
measure: Time of Cmax (Tmax)
timeFrame: t=-1.5, t=1, t=2.5, t=3.5
measure: Area under the Curve
timeFrame: t=-1.5, t=1, t=2.5,t=3.5
Locations:
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
Study officials:
affiliation: VUmc
name: Niels D Prins, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Leijenaar JF, Groeneveld GJ, Klaassen ES, Leeuwis AE, Scheltens P, Weinstein HC, van Gerven JMA, Barkhof F, van der Flier WM, Prins ND. Methylphenidate and galantamine in patients with vascular cognitive impairment-the proof-of-principle study STREAM-VCI. Alzheimers Res Ther. 2020 Jan 7;12(1):10. doi: 10.1186/s13195-019-0567-z.
citation: Leijenaar JF, Groeneveld GJ, van der Flier WM, Scheltens P, Klaassen ES, Weinstein HC, Biessels GJ, Barkhof F, Prins ND. Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI): Protocol for a Cross-Over Trial. JMIR Res Protoc. 2018 Mar 20;7(3):e80. doi: 10.2196/resprot.9192.