Symptomatic Treatment of Vascular Cognitive Impairment

Vascular Dementia Clinical Trial

— STREAM-VCI  

Official title:

Symptomatic Treatment of Vascular Cognitive Impairment

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02098824
• Other study ID #: NL45933.029.13
• Status: Recruiting
• Phase: Phase 2/Phase 3
• First received: March 14, 2014
• Last updated: April 29, 2016
• Start date: February 2014
• Est. completion date: July 2017

Study information

• Verified date: April 2016
• Source: VU University Medical Center
• Contact: Niels D Prins, MD,PhD
• Phone: +20 3017170
• Email: nd.prins[@]vumc.nl
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: July 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator)

Related Conditions & MeSH terms

• Cognition Disorders
• Dementia, Vascular
• Mild Cognitive Disorder (Vascular)
• Mild Cognitive Impairment
• Mild Cognitive Impairment (Vascular)
• Vascular Dementia

Intervention

Drug:
• Galantamine
Single administration of capsule containing 16 mg of Galantamine
• Methylphenidate
Single administration of capsule containing 10 mg of Methylphenidate
• Placebo
Single administration of capsule containing placebo

Locations

Country	Name	City	State
Netherlands	VU University Medical Center	Amsterdam

Sponsors (1)

Lead Sponsor	Collaborator
VU University Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Locations and number of cerebrovascular lesions	If patients are suitable for the study and have signed the informed consent they will undergo a MRI (structural, DTI and RS-fMRI). Visual assessment of structural cerebrovascular lesions in each patients	Single MRI scan after screening	No
Other	Structural connectivity of white matter tracts	If patients are suitable for the study and have signed the informed consent they will undergo a MRI (structural, DTI and RS-fMRI). Assessment of structural connectivity of specific white matter tracts, known to be part of the cholinergic and monoaminergic system with FLS software	Single MRI after screening	No
Other	Functional connectivity in resting state networks	If patients are suitable for the study and have signed the informed consent they will undergo a MRI (structural, DTI and RS-fMRI). Assessment functional connectivity in specific resting state networks	Single MRI, after screening	No
Other	Maximum concentration (Cmax)		t-1.5, t=1, t=2.5, t=3.5	No
Other	Time of Cmax (Tmax)		t=-1.5, t=1, t=2.5, t=3.5	No
Other	Area under the Curve		t=-1.5, t=1, t=2.5,t=3.5	No
Primary	Change on performance on executive function and on memory after active challenge	Patients will perform multiple Neurocart tests: eye movement recording, pharmaco-EEG's, visual verbal language test (VVLT), Adaptive Tracker, Facial Recognition taks, N-back and Stop Signal test of which the Adaptive Tracker and VVLT have the main focus.	timepoints 1 hour, 2.5 hours and 3.5 hours	No
Secondary	Change on performance on other Neurocart tests after active challenge	Change of performance on the other tests: N-back, Facial recognition task, Stop Signal task, eye movements and pharmaco-EEG	Timepoints 1.0 hour, 2.5 hours and 3.5 hours	No