Clinical trial NCT05565976: Dapagliflozin Effect in Cognitive Impairment in Stroke Trial
Official title: Dapagliflozin Effect in Cognitive Impairment in Stroke Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Stroke, Ischemic
Mild Cognitive Impairment
Dementia, Vascular
Metabolic Syndrome
Keywords: dapagliflozin
mortality
cognitive impairment
Lead sponsor: Universidad de Guanajuato
Sponsor class: OTHER
Collaborators: name: Hospital General León
name: Hospital General de Zona IMSS N0. 21
name: University Medical Center Groningen
First posted: 2022-10-04
Enrollment: 270
Sex: ALL
Minimum age (years): 60
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Background: Dementia is an international public health problem, affecting approximately 50,000,000 people worldwide in 2018 and will triple by 2050; furthermore, reaching an approximate cost of 4 billion dollars. Given its high worldwide prevalence and probable underdiagnosis, the international guidelines for the assessment of dementia syndromes recommend the assessment of cognitive impairment in patients over 55 years of age as part of clinical practice in patients who presented an ischemic cerebrovascular event. Several risk factors associated with cognitive impairment in cerebrovascular disease are identified in the literature: 1) demographic factors (e.g., age over 65 years and female sex); 2) risk factors present prior to the ischemic stroke (e.g., cognitive impairment, physical impairment); 3) factors utilized to assess the severity of an ischemic stroke (e.g., supratentorial location, ischemic stroke in the dominant hemisphere, recurrence of ischemic strokes); 4) post-ischemic stroke factors (e.g., delirium and seizures); and 5) factors associated with neuroimaging findings (e.g., cerebral small vessel disease, cortical atrophy, and medial temporal lobe atrophy).

This is a randomized controlled trial in individuals with an acute ischemic stroke without dementia that will be treated with 10mg dapagliflozin PO q24h for 12 months and standard treatment against only standard treatment (i.e., statins, platelet antiaggregant, and hypoglycemic medications) when appropriate. The outcome measure evaluated will be global cognitive function. Cardiovascular risk factors will be associated with cognitive decline.

Detailed description: Detailed Description: This is a double-blind, randomized, placebo-controlled, parallel-group, 12-month longitudinal study performed at a single center (Hospital General de Zona con Medicina Familiar IMSS No. 21, León Guanajuato, México) designed to investigate the effect of dapagliflozin in participants with a recent acute stroke but no history of dementia (CDR score ≤ 0.5). A total of 270 participants are to be included (i.e., 135 on each arm).

Overall objective: To assess the effect of Dapagliflozin on cardiovascular risk (i.e., the volume of epicardial fat, volume of total carotid atherosclerotic plaque, and coronary artery calcium score) in patients with ischemic cerebrovascular disease dependent on global cognitive function at a second level teaching hospital in Mexico.

Statistical analysis: Descriptive statistics will be reported for all included variables. Statistical analysis will be performed using SPSS 25 (SPSS Inc., Chicago, IL). All variables will be examined to determine the existence of outliers and whether they meet the assumptions about a Gaussian distribution. The Shapiro-Wilk tests will be used to determine normality distribution, as well as visual inspection of histograms and Q-Q plots. Demographic and clinical variables will be summarized in proportions and percentages. The categorical variables will be evaluated to determine statistical inferences with the Mann-Whitney U test. Continuous variables will be assessed for statistical inferences using t-tests (e.g., simple, paired, one, and two samples) and Levene's test to assess equality of variances. The Kaplan-Meier method will be used to calculate the distributions of mortality and development of mild amnestic cognitive disorder and dementia syndrome. The Gehan-Breslow-Wilcoxon method will be used to assess the equality of the mortality distributions and the development of mild amnestic cognitive disorder or dementia syndrome. A multivariate analysis will be performed with a Cox regression model to assess the variables that predict mortality, and the development of a mild amnestic cognitive disorder, or dementia syndrome at 6 and 12 months in case there are differences in mortality distributions. Statistical significance will be set at p=0.05 and a Bonferroni correction will be performed for multiple comparisons.

Eligibility criteria: Inclusion Criteria:

* Ages of 60 and 80 years
* Both sexes
* Cerebrovascular ischemic event within 15 days
* Clinical dementia rating score ≤ 0.5
* Signed informed consent

Exclusion Criteria:

* Type 1 diabetes mellitus
* Aphasia
* Incomplete neuropsychological battery
* Previously diagnosed dementia
* Cerebrovascular ischemic stroke older than 15 days
* History of hemorrhagic cerebrovascular event
* Neoplasia diagnosis or evidence of a metastatic process, glomerular filtration rate \< 45 mL/min at the time of inclusion
* Liver enzyme test alterations (i.e., aspartate transaminase or alanine transaminase three times greater than normal levels, total bilirubin\> 2.0 mg/dL
* Previously taking SGLT2 inhibitors
* History of diabetic ketoacidosis
* Recurrent urinary tract infections
* Psychiatric disorders (e.g., dementia, psychosis, bipolar disorder, among others).
* Less than a 12-month follow-up
* Inability to perform chest CT (e.g., claustrophobia)
* Incomplete medical files pertaining to the variables of interest
* Less than 12-month follow-up
* Decision to withdraw their participation at any moment
* Poor adherence to medical treatment
* Reported and documented disease complications or adverse effects (e.g., severe glycemic imbalance, diabetic ketoacidosis, or hyperosmolar hyperglycemic state, altered hepatic enzyme tests)

Primary outcomes:
measure: Change in Clinical Dementia Rating score as a proxy of cognitive deterioration
timeFrame: 6 and 12 months
Secondary outcomes:
measure: Number of strokes after initial cerebrovascular event
timeFrame: 12 months
Other outcomes:
measure: Adverse effects due to Dapagliflozin
timeFrame: 12 months
Locations:
city: León
country: Mexico
facility: Hospital General de Zona IMSS 21
state: Guanajuato
Study officials:
affiliation: Hospital General de Zona IMSS 21
name: Gabriela G López-Hernández, M.D.
role: STUDY_CHAIR
affiliation: Hospital General de Zona IMSS 21
name: Lizeth C Ramírez-Zamudio, M.D.
role: STUDY_CHAIR
affiliation: University Medical Center Groningen, Department of Neurology, Alzheimer Center Groningen
name: Jaime D Mondragón, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
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