Effects of Canagliflozin on Intravascular Volume and Hemodynamics

Study Overview
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Brief Summary
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RESEARCH HYPOTHESIS In subjects with T2DM and HF, effect of canagliflozin will be superior to placebo for the change from baseline in PCWP after a single dose (6 hours post-dose) and after 4 weeks. Treatment with canagliflozin will be well tolerated over 4 weeks.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, parallel-group, single-center study (Figure 1). Thirty subjects will be randomized in a 3:2 randomization ratio to canagliflozin 300 mg once daily (QD) or placebo. The study will include a 3-week pretreatment screening phase and a 4-week double-blind treatment phase.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Single-Center, Mechanistic Study to Evaluate the Effects of Canagliflozin on Intravascular Volume and Hemodynamics in Subjects With Type 2 Diabetes Mellitus and Heart Failure

Conditions
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Type2 Diabetes Mellitus, Cardiovascular Diseases

Intervention / Treatment
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* Drug: Canagliflozin 300mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: on stable doses (more than 3 months) of antihyperglycemic agents (except for an SGLT2 inhibitor and insulin) have an A1c ≥7% and ≤11% Estimated glomerular filtration rate (eGFR) must be ≥45 ml/min•1.73 m2 have an NT-proBNP ≥500 pg/mL be on a stable dose of guideline-directed HF medication (i.e., angiotensin converting enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB], or angiotensin receptor neprilysin inhibitor [ARNI], β-blocker, diuretics, and/or mineralcorticoid receptor antagonist) for at least 4 weeks be on stable antihypertensive therapy for at least 2 months Exclusion Criteria: T1DM repeated fasting plasma glucose (FPG) or fasting self-monitored blood glucose measurements ≥240 mg/dL or both during the pretreatment phase, NYHA Class IV HF status, uncontrolled hypertension as defined as systolic blood pressure (SBP) >160 or diastolic blood pressure (DBP) >100 mmHg liver disease (ALT or AST >3 x ULN) anemia Hb<10 anticipated cardiac surgery or coronary intervention within the next 3 months severe unremediated valvular heart disease major CV event (e.g., MI, cerebrovascular accident) within 3 months prior to screening visit hospitalization for HF within 2 months prior to screening visit documented atrial fibrillation history of atraumatic amputation within past 12 months of screening or critical ischemia of the lower extremity within 6 months of screening an active skin ulcer, osteomyelitis, or gangrene have an allergy to iodocyanine green and inulin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, Double-Blind, Placebo-Controlled, Single-Center, Mechanistic Study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Canagliflozin Group<br>Assuming a 25% dropout rate, 16 individuals in the canagliflozin group | Drug: Canagliflozin 300mg<br>* Canagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. It works by decreasing the amount of sugar the body absorbs, and increasing the amount of sugar that leaves the body in the urine. Administered in 300mg tablets.<br>* Other names: Invokana;|
| Placebo Comparator: Placebo Group<br>Assuming a 25% dropout rate, 11 individuals in the placebo group | Drug: Placebo<br>* Placebo for Canagliflozin<br>* Other names: Canagliflozin Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulmonary capillary wedge pressure (PCWP) | The primary efficacy endpoint will be change in PCWP from baseline to end of acute administration monitoring period (6 hours). | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulmonary capillary wedge pressure (PCWP) | The key secondary endpoint will be change in PCWP from baseline to 4 weeks. | 4 weeks |