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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05565976
Other study ID # F-2022-1005-016
Secondary ID
Status Recruiting
Phase Phase 2/Phase 3
First received
Last updated
Start date August 1, 2020
Est. completion date July 1, 2025

Study information

Verified date October 2022
Source Universidad de Guanajuato
Contact Omar Jiménez-Zarazúa, M.D.
Phone +524423421626
Email drzarazuainterna@hotmail.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 270
Est. completion date July 1, 2025
Est. primary completion date December 31, 2024
Accepts healthy volunteers No
Gender All
Age group 60 Years to 80 Years
Eligibility 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)

Study Design


Intervention

Drug:
Dapagliflozin 10mg Tab
10mg PO q24h for 12 months
Statins (Cardiovascular Agents)
Atorvastatin 20mg PO q24h or Pravastatin 20mg PO q24h or Rosuvastatin 10mg PO q24h
Platelet Antiaggregant
Clopidogrel 75mg PO q24h or Acetylsalicylic acid 100mg PO q24h
Antidiabetic
Previously established medical treatment for type 2 diabetes will be maintained.

Locations

Country Name City State
Mexico Hospital General de Zona IMSS 21 León Guanajuato

Sponsors (4)

Lead Sponsor Collaborator
Jaime Daniel Mondragon Hospital General de Zona IMSS N0. 21, Hospital General León, University Medical Center Groningen

Country where clinical trial is conducted

Mexico, 

References & Publications (22)

Bjergfelt SS, Sørensen IMH, Hjortkjær HØ, Landler N, Ballegaard ELF, Biering-Sørensen T, Kofoed KF, Lange T, Feldt-Rasmussen B, Sillesen H, Christoffersen C, Bro S. Carotid plaque thickness is increased in chronic kidney disease and associated with caroti — View Citation

Cherney DZI, Dekkers CCJ, Barbour SJ, Cattran D, Abdul Gafor AH, Greasley PJ, Laverman GD, Lim SK, Di Tanna GL, Reich HN, Vervloet MG, Wong MG, Gansevoort RT, Heerspink HJL; DIAMOND investigators. Effects of the SGLT2 inhibitor dapagliflozin on proteinuri — View Citation

Dekkers CCJ, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, Heerspink HJL. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes Metab. 2018 Aug;20(8):1988-1993. doi: 10.1111/dom.13301. Epub 2018 Apr 23 — View Citation

Dhillon S. Dapagliflozin: A Review in Type 2 Diabetes. Drugs. 2019 Jul;79(10):1135-1146. doi: 10.1007/s40265-019-01148-3. Review. Erratum in: Drugs. 2019 Dec;79(18):2013. — View Citation

Díaz-Rodríguez E, Agra RM, Fernández ÁL, Adrio B, García-Caballero T, González-Juanatey JR, Eiras S. Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation abil — View Citation

Esterline R, Oscarsson J, Burns J. A role for sodium glucose cotransporter 2 inhibitors (SGLT2is) in the treatment of Alzheimer's disease? Int Rev Neurobiol. 2020;155:113-140. doi: 10.1016/bs.irn.2020.03.018. Epub 2020 Aug 11. Review. — View Citation

Esterline RL, Vaag A, Oscarsson J, Vora J. MECHANISMS IN ENDOCRINOLOGY: SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism? Eur J Endocrinol. 2018 Apr;178(4):R113-R125. doi: 10.1530/EJE-17-0832. Epub 2018 Jan 25. Review. — View Citation

Fani L, van Dam-Nolen DHK, Vernooij M, Kavousi M, van der Lugt A, Bos D. Circulatory markers of immunity and carotid atherosclerotic plaque. Atherosclerosis. 2021 May;325:69-74. doi: 10.1016/j.atherosclerosis.2021.03.040. Epub 2021 Apr 7. — View Citation

Iacobellis G, Gra-Menendez S. Effects of Dapagliflozin on Epicardial Fat Thickness in Patients with Type 2 Diabetes and Obesity. Obesity (Silver Spring). 2020 Jun;28(6):1068-1074. doi: 10.1002/oby.22798. Epub 2020 Apr 30. — View Citation

Iadecola C, Duering M, Hachinski V, Joutel A, Pendlebury ST, Schneider JA, Dichgans M. Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019 Jul 2;73(25):3326-3344. doi: 10.1016/j.jacc.2019.04.034. Review. — View Citation

Ihara M, Saito S. Drug Repositioning for Alzheimer's Disease: Finding Hidden Clues in Old Drugs. J Alzheimers Dis. 2020;74(4):1013-1028. doi: 10.3233/JAD-200049. Review. — View Citation

Jabbour S, Seufert J, Scheen A, Bailey CJ, Karup C, Langkilde AM. Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018 Mar;20(3):620-628. doi: 10.1111/dom.1 — View Citation

Jellinger KA, Attems J. Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol. 2010 Apr;119(4):421-33. doi: 10.1007/s00401-010-0654-5. Epub 2010 Mar 4. — View Citation

McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman C — View Citation

Mijajlovic MD, Pavlovic A, Brainin M, Heiss WD, Quinn TJ, Ihle-Hansen HB, Hermann DM, Assayag EB, Richard E, Thiel A, Kliper E, Shin YI, Kim YH, Choi S, Jung S, Lee YB, Sinanovic O, Levine DA, Schlesinger I, Mead G, Miloševic V, Leys D, Hagberg G, Ursin M — View Citation

Mohamed Fuad Z, Mahadzir H, Syed Zakaria SZ, Mohamed Ibrahim N. Frequency of Cognitive Impairment Among Malaysian Elderly Patients Following First Ischaemic Stroke-A Case Control Study. Front Public Health. 2020 Nov 12;8:577940. doi: 10.3389/fpubh.2020.57 — View Citation

Sato T, Aizawa Y, Yuasa S, Fujita S, Ikeda Y, Okabe M. The Effect of Dapagliflozin Treatment on Epicardial Adipose Tissue Volume and P-Wave Indices: An Ad-hoc Analysis of The Previous Randomized Clinical Trial. J Atheroscler Thromb. 2020 Dec 1;27(12):1348 — View Citation

Serena J, Irimia P, Calleja S, Blanco M, Vivancos J, Ayo-Martín O; Representación de la Sociedad Española de Neurosonología (SONES). [Ultrasound measurement of carotid stenosis: recommendations from the Spanish Society of Neurosonology]. Neurologia. 2013 — View Citation

Suda S, Nishimura T, Ishiwata A, Muraga K, Aoki J, Kanamaru T, Suzuki K, Sakamoto Y, Katano T, Nishiyama Y, Mishina M, Kimura K. Early Cognitive Impairment after Minor Stroke: Associated Factors and Functional Outcome. J Stroke Cerebrovasc Dis. 2020 May;2 — View Citation

Uemura MT, Maki T, Ihara M, Lee VMY, Trojanowski JQ. Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia. Front Aging Neurosci. 2020 Apr 14;12:80. doi: 10.3389/fnagi.2020.00080. eCollection 2020. Review. — View Citation

van der Flier WM, Skoog I, Schneider JA, Pantoni L, Mok V, Chen CLH, Scheltens P. Vascular cognitive impairment. Nat Rev Dis Primers. 2018 Feb 15;4:18003. doi: 10.1038/nrdp.2018.3. Review. — View Citation

Zlokovic BV, Gottesman RF, Bernstein KE, Seshadri S, McKee A, Snyder H, Greenberg SM, Yaffe K, Schaffer CB, Yuan C, Hughes TM, Daemen MJ, Williamson JD, González HM, Schneider J, Wellington CL, Katusic ZS, Stoeckel L, Koenig JI, Corriveau RA, Fine L, Gali — View Citation

* Note: There are 22 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Other Adverse effects due to Dapagliflozin Adverse effects reported due to the use of dapagliflozin 12 months
Primary Change in Clinical Dementia Rating score as a proxy of cognitive deterioration Time-to-event analysis using the Kaplan-meier survival analysis via increase in Clinical Dementia Rating score greter or equal to 0.5 6 and 12 months
Secondary Number of strokes after initial cerebrovascular event Independent stroke events 12 months
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