Type 2 Diabetes MellitusPhase 4NCT02964585

Role of Canagliflozin on CD34+ Cells in Patients With Type 2 Diabetes

A Phase 4 study testing Canagliflozin in people with Type 2 Diabetes Mellitus, run by George Washington University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The investigators hypothesize that Cana may be able to improve number and function of CD34+ endothelial progenitor cells. The investigators also propose that this expected cardiovascular benefit is independent of HbA1C reduction. Subjects will begin taking 100 mg of Cana or placebo after initial 4 weeks. Read more about this study

Who is it for?: Ages 30 to 70 years
Conditions the study is for: Type 2 Diabetes Mellitus
What is being tested?: Canagliflozin
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 34 participants
Where: 1 siteUnited States
Study dates: Nov 2016to Sep 2020
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 30 to 70 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Age 30-70 years
Currently treated with any combination of the following anti-diabetic therapies: metformin (1-2 grams), insulin, GLP-1 agonists, a DPP-IV inhibitor, or sulfonylureas
Hemoglobin A1C (HbA1C) between 7.0% and 10.0%
Body Mass Index (BMI) between 25 and 39.9 kg/m^2 (both inclusive)

Who cannot join

Type 1 diabetes
History of hyperosmolar nonketotic coma
History of diabetic ketoacidosis in the last 3 months
Abnormal CBC that is judged by physician to be unsafe to enroll or low hematocrit (<28 UNITS).
History of pancreatitis
History of diabetic ketoacidosis in the last 3 months

Show all 37Show fewer

History of cancer (except basal cell carcinoma and cancer that is cured or not active or being treated in the past 5 years)
Heart attack or stroke within 6 months of screening
Clinically significant coronary and/or peripheral vascular disease that would be unsafe to enroll in the study.
Statin use started or dose change in the last 3 months
CKD Stages 3,4 and 5
Use of oral or injectable anti-diabetic medication other than any combination of the following anti-diabetic therapies: metformin (1-2 grams), insulin, GLP-1 agonists, a DPP-IV inhibitor, or sulfonylureas currently, or in the past 1 month.
Use of consistent long-term steroid medication (oral, inhaled, injected) within the last 3 months
Uncontrolled inflammatory disease, or current chronic use of anti-inflammatory drugs within the last 3 months. This will be judged on a case by case basis by the PI
Implanted devices (e.g., pacemakers) that may interact with Body Composition scale
Untreated Systolic Blood Pressure > 150 mmHg and diastolic Blood Pressure > 90 mmHg
Active wounds or recent surgery within 3 months
Untreated hyper/hypothyroidism
Physical and Laboratory Test Findings:
Pre-existing liver disease and/or ALT and AST >2.5X's UNL
Serum creatinine levels ≥2.0
Estimated CrCl < 60 mL/min (measured by eGFR value)
Triglycerides >450 mg/dL
Allergies and Adverse Drug Reactions:
Subjects with a history of any serious hypersensitivity reaction to Cana or another SGLT2 inhibitor.
Sex and Reproductive Status:
Women in reproductive age group will be included in the study but encouraged to use contraceptive method to avoid pregnancy within 16 weeks of study duration.
Women who are pregnant or breast-feeding will be excluded.
Other Exclusion Criteria:
Prisoners or subjects who are involuntarily incarcerated.
Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
Patients who are active smokers
Patients who are pregnant
Nursing women
Post-menopausal women who are on estrogen hormone replacement therapy will be excluded.
Patients on low dose oral contraceptives will be allowed to participate as these formulations contain very low amounts of estrogens.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.

Trial locations and contacts

1 site in 1 country.

United States1 site

The George Washington University Medical Faculty Associates
Washington D.C., District of Columbia, 20037

Other trials in United States

About this study

Official title: Role of Canagliflozin on Gene Expression and Function of CD34+ Endothelial Progenitor Cells and Renal Function in Patients With Type 2 Diabetes

Subjects will begin taking 100 mg of Cana or placebo after initial 4 weeks. Subjects will be withdrawn from the study if the medication or placebo is not tolerated.

Read the detailed description

Diabetes affects more than 11% of adults in the United States and this is projected to nearly double by 2025. Both diabetes and obesity are associated with endothelial dysfunction, oxidative stress, endothelial cell inflammation, cardiovascular pro-thrombotic states and are the most common causes of kidney disease. Use of a sodium-glucose linked transporter (SGLT-2) inhibitor has shown promise in improving glycemic control, weight reduction, hypertension and even changes in circulating Renin-angiotensin-aldosterone system (RAAS) and nitric oxide (NO). However, whether these group of drugs have any effect on cardiovascular disease (CVD) risk modification or on endothelium or endothelial progenitor cells as a surrogate of cardiovascular and renal risk outcome measure, is unclear.

The investigators have previously shown that CD34+ cells, derived from peripheral blood can act as a cellular biomarker that is more reliable than serum based markers for CVD risk estimation. Serum based inflammatory markers are not useful until the endothelium is already damaged and inflamed. Such serum based biomarkers takes several months to change and gives no preventive and predictable information as to whether a particular medication may affect future endothelium. This is why the study of endothelium progenitors is crucial. In the investigators' previous study of a prediabetes population with an aerobic exercise intervention, the investigators have demonstrated that CD34+ cells are responsive to a change in therapy or intervention within 2-4 weeks and can be used as a reliable non serum based cellular bio-marker. CD34+ cells or endothelial progenitor cells have been used clinically to improve collateral circulation and have been extensively studied as a robust cardiovascular biomarker. Therefore studying CD34+ cells in patients, with or without Canagliflozin (Cana) can give vital information about the medication and its effect on endothelium. This is particularly important as another SGLT2 inhibitor Empagliflozin has shown unparalleled positive cardiovascular effects with an oral hypoglycemic agent. Of course, the question arises whether this clinical trial effect is secondary to glucose effect or direct effect of SGLT2 inhibitor on endothelium.

Multiple glucose transporters have been identified in human cells these include GLUTs, SGLTs and even taste receptors (such as TLR2 and TLR3). The investigators know SGLT transporters are present in tubular cells and clearly blocking of SGLT2 in these cells is beneficial. Information on glucose transporter in stem or progenitor cells is almost nil. In our lab the investigators have shown presence of GLUT1, SGLTs and TLR3 on CD34+ cells. The investigators have also demonstrated that hyperglycemia is toxic to CD34+ cells, more than CD31+ positive mature endothelial cells. The investigators hypothesize that blocking SGLT2 in CD34+ cells will be beneficial rather than detrimental. As far as glucose uptake in CD34+ cells are concerned other glucose transporters should be sufficient, in fact lesser amount of glucose entry in a hyperglycemic milieu (type 2 DM patients) may be less pro-inflammatory and less pro-apoptotic.

Our preliminary data indicates that mRNA gene expression of both SGLT1 and SGLT2 are noted on human CD34+ cells however only SGLT2 mRNA gene expression is up-regulated several fold in human CD34+ cells in presence of hyperglycemia (20mM glucose). However non primary commercially obtained human endothelium (HUVEC) do not show similar results. An explanation could be SGLT2 expression decreases as the cell transitions from progenitor to mature endothelium. From these results the investigators believe SGLT2 inhibitor will be effective on progenitors and not mature endothelium. The investigators therefore hypothesize that CD34+ cells will be an ideal biomarker to study the effect of the drug. It is possible that Cana, by blocking SGLT2 receptors, may influence other CD34+ cell surface receptors including other glucose transporters and influence its function (most importantly migration). If a particular medication positively influences stem/progenitor cell migration then that medication can positively influence endothelial dysfunction and vascular complications from diabetes. The investigators are particularly interested to note effect of Canagliflozin, a SGLT2 inhibitor on other glucose transporters such as GLUT 1 and 4 while looking at SGLT 1 and 2 on CD34+ cells. It will be helpful to discern these effects particularly when choice of oral diabetic medication in a type 2 diabetes population is practically limited to metformin, DPP4 inhibitors and SGLT2 inhibitors. The investigators plan to investigate the effect of Cana on CD34+ cells, in a placebo matched study. The investigators plan to recruit subjects with type 2 diabetes with the following characteristics: 1) overweight, mild and moderately obese (BMI=25.0-39.9); 2) individuals with early type 2 diabetes (≤15 years) with inadequate control, HbA1C= 7.0 to 10.0%, on Metformin (1-2 grams/day) 3) with no history or presence of macrovascular complication and CKD no higher than stage 2. The subjects will be on Metformin as per ADA, Metformin is the 1st line of care along with life-style modification. While Metformin on its own may affect inflammatory biomarkers, the effect is minimal at best, particularly in presence of CKD and endothelial dysfunction. Also both placebo and the cana group will be on Metformin.

The investigators will recruit a total of 40 patients (20 individuals/per group) with approximately a 20% drop out rate over two years and the investigators hope to retain 32 individuals (16/group). Individuals in each group will be matched by sex, age, and race. Participants will be assessed at baseline (week 0), and at 2 and 4 months of drug intake.

Conditions: Type 2 Diabetes Mellitus
Being tested: Canagliflozin, Placebo
Keywords: Type 2 Diabetes Mellitus, Endothelial Cells, Cellular Biomarker, Endothelial Dysfunction, CD34+, Impaired renal function
Medical subject headings: Diabetes Mellitus, Type 2, Renal Insufficiency

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

CanagliflozinDrug
Also called INVOKANA
100 mg
PlaceboDrug
1 tablet daily for 16 weeks

Study groups in NCT02964585
Study group	Role	What they receive
Active Arm	Active comparator	100 mg of Canagliflozin for 16 weeks Receives: Drug: Canagliflozin
Placebo Arm	Placebo comparator	Placebo for 16 weeks Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Protein Expression)
To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before [13,14]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.
Measured: 16 weeks post Canagliflozin treatment reported
Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Percentages)
To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before [13,14]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.
Measured: 16 weeks post Canagliflozin treatment reported
Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Counts)
To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before [13,14]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.
Measured: 16 weeks post Canagliflozin treatment reported
Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Proliferation)
To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before [13,14]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.
Measured: 16 weeks post Canagliflozin treatment reported

Secondary outcomes (14)

Serum Endothelial Inflammatory Markers (1)
IL-6, and TNF-alpha
Measured: measured at 8 and 16 (reported) weeks post treatment
Fasting Lipid Profile
Measured from a serum blood Lipid Panel: cholesterol and serum ketone bodies
Measured: 16 weeks post Canagliflozin treatment reported (also measured at 8 weeks)
Glycemic Control (HbA1C)
As determined by HbA1C values
Measured: 16 weeks post Canagliflozin treatment reported
BMI
Determined as weight in kg divided by height in meters squared
Measured: 16 weeks post Canagliflozin treatment
Resting Metabolic Rate (RMR)
Using ReeVue (trademark) machine, with or without SGLT2 inhibitor therapy to ascertain if Cana has any effect on RMR. Other related trials have shown weight loss but effect on metabolic rate has not been studied .
Measured: 16 weeks post Canagliflozin treatment
Pulse Wave Velocity
Vessel health assessed by using arterial tonometry with the SphygmoCor CP system from ATCOR .
Measured: 16 weeks post Canagliflozin treatment reported (also measured at 8 weeks)
Serum Endothelial Inflammatory Markers (2)
Highly selective C-reactive protein (hs-CRP)
Measured: measured at 8 and 16 (reported) weeks post treatment
Glycemic Control
Measured from blood glucose values (fasting) during visit
Measured: 16 weeks post Canagliflozin treatment reported
Body Fat Percentage
Measured using a Tanita body composition scale
Measured: 16 weeks post Canagliflozin treatment
Augmentation Index (Pulse Wave Analysis)
Vessel health assessed by using arterial tonometry with the SphygmoCor CP system from ATCOR. Higher values generally correlate with increased cardiovascular risk.
Measured: 16 weeks post Canagliflozin treatment reported (also measured at 8 weeks)
Kidney Function Markers
Creatinine Clearance and Kidney Function measured from compiled results from a urine sample and blood tests
Measured: 16 weeks post Canagliflozin treatment reported
Creatinine (Urine)
Creatinine Clearance and Kidney Function measured from compiled results from a urine sample and blood tests
Measured: 16 weeks post Canagliflozin treatment reported
Microalbumin
Creatinine Clearance and Kidney Function measured from compiled results from a urine sample and blood tests
Measured: 16 weeks post Canagliflozin treatment reported
eGFR
Creatinine Clearance and Kidney Function measured from compiled results from a urine sample and blood tests
Measured: 16 weeks post Canagliflozin treatment reported

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Nov 2016Sep 2020

First posted16 Nov 2016 (estimated)
Study startNov 2016
Primary completionJan 2020
Study completionSep 2020

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (13)Papers the sponsor has linked to this study.
Other trials for Type 2 Diabetes MellitusStudies of the same condition, open and under way.
More trials run by George Washington UniversityThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 34 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02964585
Sponsor's protocol ID: GW-CANA-081635
Status last verified: Nov 2022
First submitted: 6 Oct 2016
Last updated: 7 Dec 2022
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

Sen S, Strappe PM, O'Brien T. Gene transfer in endothelial dysfunction and hypertension. Methods Mol Med. 2005;108:299-314. doi: 10.1385/1-59259-850-1:299.
PubMed 16028691
Krenning G, Dankers PY, Drouven JW, Waanders F, Franssen CF, van Luyn MJ, Harmsen MC, Popa ER. Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease. Am J Physiol Renal Physiol. 2009 Jun;296(6):F1314-22. doi: 10.1152/ajprenal.90755.2008. Epub 2009 Apr 1.
PubMed 19339628
Department of Health and Human Services, NIH and National Center for Chronic Disease Prevention and Health Promotion, "National Diabetes Statistics: 2007 and 2011 Fact Sheet." 2011
American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. No abstract available.
PubMed 24357209
Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, de Boer IH. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013 Feb;24(2):302-8. doi: 10.1681/ASN.2012070718. Epub 2013 Jan 29.
PubMed 23362314
Rask-Madsen C, King GL. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):46-56. doi: 10.1038/ncpendmet0366.
PubMed 17179929
Stanton RC. Sodium glucose transport 2 (SGLT2) inhibition decreases glomerular hyperfiltration: is there a role for SGLT2 inhibitors in diabetic kidney disease? Circulation. 2014 Feb 4;129(5):542-4. doi: 10.1161/CIRCULATIONAHA.113.007071. Epub 2013 Dec 13. No abstract available.
PubMed 24334174
Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014 May;8(5):330-9. doi: 10.1016/j.jash.2014.02.003. Epub 2014 Feb 12.
PubMed 24631482
Sabyasachi Sen, Sarah Witkowski, Ann Lagoy, Ashequl M. Islam: A six-week home exercise program improves endothelial function and CD34+ circulating progenitor cells in patients with pre-diabetes. J Endocrinol Metab.2015; 5 (1-2):163-171, doi: http://dx.doi.org/10.14740/jem273w.
Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005 Sep 8;353(10):999-1007. doi: 10.1056/NEJMoa043814.
PubMed 16148285
Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, Durgin M, Poh KK, Weinstein R, Kearney M, Chaudhry M, Burg A, Eaton L, Heyd L, Thorne T, Shturman L, Hoffmeister P, Story K, Zak V, Dowling D, Traverse JH, Olson RE, Flanagan J, Sodano D, Murayama T, Kawamoto A, Kusano KF, Wollins J, Welt F, Shah P, Soukas P, Asahara T, Henry TD. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007 Jun 26;115(25):3165-72. doi: 10.1161/CIRCULATIONAHA.106.687376. Epub 2007 Jun 11.
PubMed 17562958
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
PubMed 26378978
Nandula SR, Kundu N, Awal HB, Brichacek B, Fakhri M, Aimalla N, Elzarki A, Amdur RL, Sen S. Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes. Cardiovasc Diabetol. 2021 Feb 13;20(1):44. doi: 10.1186/s12933-021-01235-4.
PubMed 33581737

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 7 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Role of Canagliflozin on Gene Expression and Function of CD34+ Endothelial Progenitor Cells and Renal Function in Patients With Type 2 Diabetes
ClinicalTrials.gov ID: NCT02964585
Acronym / sponsor ID: GW-CANA-081635
Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 Diabetes Mellitus, Endothelial Cells, Cellular Biomarker, Endothelial Dysfunction, CD34+, Impaired renal function
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 34 participants (actual)
Lead sponsor: George Washington UniversityUniversity, hospital or other
Collaborators: Janssen Scientific Affairs, LLC
Study start: Nov 2016 (actual)
Primary completion: Jan 2020 (actual)
Study completion: Sep 2020 (actual)
First posted: 16 Nov 2016 (estimated)
Results: Posted 7 Dec 2022

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Subjects will begin taking 100 mg of Cana or placebo after initial 4 weeks. Subjects will be withdrawn from the study if the medication or placebo is not tolerated.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (participant, investigator)
Number of arms: 2

Arm	Type	Receives
Active Arm	Active comparator	Drug: Canagliflozin100 mg of Canagliflozin for 16 weeks
Placebo Arm	Placebo comparator	Drug: PlaceboPlacebo for 16 weeks

Who may qualify

Ages: 30 to 70 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (4 listed)

Age 30-70 years
Currently treated with any combination of the following anti-diabetic therapies: metformin (1-2 grams), insulin, GLP-1 agonists, a DPP-IV inhibitor, or sulfonylureas
Hemoglobin A1C (HbA1C) between 7.0% and 10.0%
Body Mass Index (BMI) between 25 and 39.9 kg/m^2 (both inclusive)

Key exclusion criteria (37 listed)

Type 1 diabetes
History of hyperosmolar nonketotic coma
History of diabetic ketoacidosis in the last 3 months
Abnormal CBC that is judged by physician to be unsafe to enroll or low hematocrit (<28 UNITS).
History of pancreatitis

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
CanagliflozinAlso: INVOKANA100 mg	Drug	Active Arm
Placebo1 tablet daily for 16 weeks	Drug	Placebo Arm

Primary outcome

Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Protein Expression)
Time frame: 16 weeks post Canagliflozin treatment reported
To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before [13,14]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.
Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Percentages)
Time frame: 16 weeks post Canagliflozin treatment reported
To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before [13,14]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.
Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Counts)
Time frame: 16 weeks post Canagliflozin treatment reported
To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before [13,14]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.
Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Proliferation)
Time frame: 16 weeks post Canagliflozin treatment reported
To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before [13,14]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.

14 secondary outcomes

Serum Endothelial Inflammatory Markers (1)
Time frame: measured at 8 and 16 (reported) weeks post treatment
Fasting Lipid Profile
Time frame: 16 weeks post Canagliflozin treatment reported (also measured at 8 weeks)
Glycemic Control (HbA1C)
Time frame: 16 weeks post Canagliflozin treatment reported
BMI
Time frame: 16 weeks post Canagliflozin treatment
Resting Metabolic Rate (RMR)
Time frame: 16 weeks post Canagliflozin treatment
Pulse Wave Velocity
Time frame: 16 weeks post Canagliflozin treatment reported (also measured at 8 weeks)
Serum Endothelial Inflammatory Markers (2)
Time frame: measured at 8 and 16 (reported) weeks post treatment
Glycemic Control
Time frame: 16 weeks post Canagliflozin treatment reported
Body Fat Percentage
Time frame: 16 weeks post Canagliflozin treatment
Augmentation Index (Pulse Wave Analysis)
Time frame: 16 weeks post Canagliflozin treatment reported (also measured at 8 weeks)
Kidney Function Markers
Time frame: 16 weeks post Canagliflozin treatment reported
Creatinine (Urine)
Time frame: 16 weeks post Canagliflozin treatment reported
Microalbumin
Time frame: 16 weeks post Canagliflozin treatment reported
eGFR
Time frame: 16 weeks post Canagliflozin treatment reported

Results and safety

Results posted to the registry on 7 Dec 2022, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Active Arm	15	15
Placebo Arm	14	14

Primary outcome: Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Protein Expression)

Time frame: 16 weeks post Canagliflozin treatment reported. Mean (Standard Deviation). Unit: ng/mL in serum

Measure	Active Arm n = 15	Placebo Arm n = 14
CXCL12 Expression	0.63 (0.18)	0.33 (0.17)
CXCR4 Expression	1.58 (0.18)	0.90 (0.18)
EDN1	2.10 (0.27)	1.03 (0.29)
VEGEF-A	1.12 (0.19)	0.83 (0.19)
PECAM	1.28 (0.12)	0.89 (0.12)
KDR	1.16 (0.2)	0.5 (0.2)
NOS3	0.34 (0.21)	-0.25 (0.21)
Catalase	0.20 (0.26)	-0.61 (0.26)

Primary outcome: Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Percentages)

Time frame: 16 weeks post Canagliflozin treatment reported. Mean (Standard Deviation). Unit: percentage of MNCs

Measure	Active Arm n = 15	Placebo Arm n = 14
Percent of CD34+	0.93 (0.17)	1.23 (0.21)
Percent of CD31+	2.58 (0.35)	2.16 (0.43)
Percent CD34+ and CD184+	0.37 (0.09)	0.61 (0.11)

Primary outcome: Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Counts)

Time frame: 16 weeks post Canagliflozin treatment reported. Mean (Standard Deviation). Unit: cells*10^6/mL

Measure	Active Arm n = 15	Placebo Arm n = 14
Mean MNC count	155.09 (15.54)	155.09 (16.08)
Mean CD34+ve cell count (x100)	2682.93 (491.44)	3157.36 (508.69)

Primary outcome: Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Proliferation)

Time frame: 16 weeks post Canagliflozin treatment reported. Mean (Standard Deviation). Unit: Colony forming units (CFU)

Measure	Active Arm n = 15	Placebo Arm n = 14
Value	7.53 (1.89)	13.69 (2.10)

14 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse event data was collected from signing of consent form to 30 days after last treatment day, approximately 20 weeks in total.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Active Arm	0 of 15 (0%)	0 of 15 (0%)	0 of 15
Placebo Arm	0 of 14 (0%)	0 of 14 (0%)	0 of 14

Limitations and caveats (from the sponsor): Limitations of our pilot study may include the relatively short 16-week Canagliflozin therapy, which may be inadequate to see significant changes in certain clinical and cellular parameters. This maybe also because of the small sample size. Further studies with a larger population and longer duration may be helpful to further define the mechanisms behind our findings.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 7 Dec 2022.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 16028691Sen S, Strappe PM, O'Brien T. Gene transfer in endothelial dysfunction and hypertension. Methods Mol Med. 2005;108:299-314. doi: 10.1385/1-59259-850-1:299.
Background: PubMed 19339628Krenning G, Dankers PY, Drouven JW, Waanders F, Franssen CF, van Luyn MJ, Harmsen MC, Popa ER. Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease. Am J Physiol Renal Physiol. 2009 Jun;296(6):F1314-22. doi: 10.1152/ajprenal.90755.2008. Epub 2009 Apr 1.
BackgroundDepartment of Health and Human Services, NIH and National Center for Chronic Disease Prevention and Health Promotion, "National Diabetes Statistics: 2007 and 2011 Fact Sheet." 2011
Background: PubMed 24357209American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. No abstract available.
Background: PubMed 23362314Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, de Boer IH. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013 Feb;24(2):302-8. doi: 10.1681/ASN.2012070718. Epub 2013 Jan 29.
Background: PubMed 17179929Rask-Madsen C, King GL. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):46-56. doi: 10.1038/ncpendmet0366.
Background: PubMed 24334174Stanton RC. Sodium glucose transport 2 (SGLT2) inhibition decreases glomerular hyperfiltration: is there a role for SGLT2 inhibitors in diabetic kidney disease? Circulation. 2014 Feb 4;129(5):542-4. doi: 10.1161/CIRCULATIONAHA.113.007071. Epub 2013 Dec 13. No abstract available.
Background: PubMed 24631482Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014 May;8(5):330-9. doi: 10.1016/j.jash.2014.02.003. Epub 2014 Feb 12.
BackgroundSabyasachi Sen, Sarah Witkowski, Ann Lagoy, Ashequl M. Islam: A six-week home exercise program improves endothelial function and CD34+ circulating progenitor cells in patients with pre-diabetes. J Endocrinol Metab.2015; 5 (1-2):163-171, doi: http://dx.doi.org/10.14740/jem273w.
Background: PubMed 16148285Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005 Sep 8;353(10):999-1007. doi: 10.1056/NEJMoa043814.
Background: PubMed 17562958Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, Durgin M, Poh KK, Weinstein R, Kearney M, Chaudhry M, Burg A, Eaton L, Heyd L, Thorne T, Shturman L, Hoffmeister P, Story K, Zak V, Dowling D, Traverse JH, Olson RE, Flanagan J, Sodano D, Murayama T, Kawamoto A, Kusano KF, Wollins J, Welt F, Shah P, Soukas P, Asahara T, Henry TD. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007 Jun 26;115(25):3165-72. doi: 10.1161/CIRCULATIONAHA.106.687376. Epub 2007 Jun 11.
Background: PubMed 26378978Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Sabyasachi Sen, MD, PhD principal investigator

Medical Faculty Associates

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Canagliflozin in people with Type 2 Diabetes Mellitus, run by George Washington University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 7 Dec 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Protein Expression) (time frame: 16 weeks post Canagliflozin treatment reported). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02964585, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Dec 2022.