CARAT: Canagliflozin vs. Placebo for Post Bariatric Patients With Persistent Type 2 Diabetes

Study Overview
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Brief Summary
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This is a prospective, randomized clinical trial for patients with recurrent type 2 diabetes post-gastric bypass surgery that will compare a 6 month course of canagliflozin monotherapy vs. placebo on clinical outcomes of type 2 diabetes.

Detailed Description
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Following consent and a screening visit to assess eligibility and clinical status (i.e. historical, physical and biochemical parameters including glycemic control and a pregnancy test in females), a baseline visit with diabetes educator will take place to provide standard diabetes education, nutrition and exercise prescription. Nutritional assessment for vitamin/mineral deficiency will be performed per clinical care guidelines at the screening visit. Subjects will be asked to take nutritional supplements (i.e. vitamins and minerals) per current clinical guidelines for post-bariatric patients. Stable doses of supplements will be established for at least 2 weeks prior to randomization. Thirty-six subjects with recurrent diabetes that are naïve to hypoglycemic agents with HbA1c greater than or equal to 6.5% and less than 10% will be randomly assigned to a six month course of a) canagliflozin 100mg for 2 weeks titrated up to 300 mg daily (N = 24) vs. placebo (n= 12) at the randomization. Patients taking an anti-diabetic medication will be asked to wash out for 8 weeks prior to the randomization visit. At randomization, biochemical assessment of glycemic parameters (fasting glucose, HbA1c), lipid panel, complete metabolic panel, uric acid, leptin, total and HMW adiponectin, C-reactive protein and urine for albumin/creatinine ratio will be performed. Dual-energy x-ray absorptiometry (DXA) scan will be performed for body fat composition. Following randomization, subjects will be clinically evaluated at three office visits at 6 weeks, 3 and 6 months by PI and/or the research staff. The primary outcome measures at 6 months post-randomization include HbA1c followed by the change in HbA1c from randomization. Secondary measures include fasting glucose, BMI, change in body weight, blood pressure, lipid profile. Symptomatic hypoglycemia (blood glucose < 70) and drug related side effects (i.e. mycotic genital infections, urinary tract infection) will be monitored with adverse event reporting. Metabolic testing in all subjects at randomization and at 6 months will include a DXA scan for body fat composition and blood for leptin and adiponectin levels. Rescue glucose lowering therapy will be provided for the control group for blood glucose >250 mg/dl. If chronic uncontrolled hyperglycemia (HbA1c >10%) occurs then basal bolus insulin will be implemented.

Official Title
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Canagliflozin vs. Placebo for Post Bariatric Patients With Persistent Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2, Obesity

Intervention / Treatment
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* Drug: canagliflozin
* Drug: Placebo (for canagliflozin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post Roux-n-Y gastric bypass (RYGB) surgery and sleeve gastrectomy (SG) patients who underwent surgery >1 and <15 years ago in the Cleveland surrounding area Age 20-75 years of age Type II Diabetes Mellitus (D2M) diagnosis (history, medication usage, biochemical criteria) prior to and after surgery; after surgery, defined by a single HbA1c of greater or equal to 6.5% at consent and screening. Metformin patients must have an HbA1c greater than or equal to 6.5% but less than or equal to 10% at randomization; for diet controlled patients (i.e. not on any T2D medication), HbA1c must be greater than or equal to 6.5% at randomization. Patient reporting of improvement in T2D status or objective improvements in T2D status at any time post-surgery. estimated glomerular filtration rate (eGFR) ≥ 60mL/min prior to randomization Has the ability and willingness to provide informed consent. Is able to understand the options and to comply with the requirements of each program Female subject agrees to have a serum pregnancy test at screening. A negative serum pregnancy test result is required prior to randomization. Female patients must agree to use a reliable method of contraception for 6 months or duration of intervention Patients taking an anti-diabetic medication, except insulin, are eligible and must agree to washout for 8 weeks prior to the randomization visit. Exclusion Criteria: Type 1 diabetes indicated by history of diabetic ketoacidosis and lack of remission in response to bariatric surgery Other post bariatric procedures (banding, duodenal switch, biliopancreatic diversion) Current use of insulin. End organ diabetic complications (renal failure, cardiomyopathy, severe neuropathy/foot ulcers) Documented severe or unstable depression/anxiety or eating disorder that would not enable patient to adhere to anti-diabetic treatment Clinical contraindications to use canagliflozin, i.e., history of bladder cancer, Child-Pugh class C

Ages Eligible for Study
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Minimum Age: 20 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study Drug (canagliflozin)<br>Subjects randomized to study drug will be assigned a six month course starting on canagliflozin 100 mg for two weeks titrated up to 300 mg daily (n= 24). | Drug: canagliflozin<br>* encapsulated (gelatin capsule).<br>* Other names: Invokana;|
| Placebo Comparator: Placebo<br>Subjects randomized to placebo will be assigned a six month course of one placebo pill daily (n =12). | Drug: Placebo (for canagliflozin)<br>* encapsulated (gelatin capsule). The placebo capsule filler is called micro-crystalline cellulose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change at Six Months Versus Baseline in Hemoglobin A1c Value (%) | The change in hemoglobin A1c from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Glucose From Randomization | The change in fasting glucose from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. | 6 months | 
| Change in Body Weight at Six Months Compared to Baseline | The change in body weight from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. | 6 months | 
| Change in Total Cholesterol | The change in total cholesterol from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery | 6 months | 
| Change in Diastolic Blood Pressure at Six Months Compared to Baseline | The change in diastolic blood pressure from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery | 6 months | 
| Change in Adiponectin Levels at 6 Months Compared to Randomization | The change in adiponectin levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. | 6 months | 
| Change in Leptin Levels at 6 Months Compared to Baseline | Change in leptin levels at 6 months compared to baseline The change in leptin levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. | 6 months | 
| Change in CRP Levels at 6 Months Compared to Baseline | The change in C-reactive protein levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. | 6 months | 
| Number of Participants Who Reported Hypoglycemia From Each Group (at a Frequency of 1 Episode) | The number of participants who reported symptomatic hypoglycemia episodes from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. | 6 months | 
| Change in Percent Body Fat as Measured by DEXA Scan at 6 Months Compared to Randomization | The change in body fat from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. | 6 months | 
| Change in Systolic Blood Pressure at 6 Months Compared to Baseline | The Change in Systolic Blood Pressure From Randomization Following the 6 Month Administration of Canagliflozin vs. Placebo in Patients With Type 2 Diabetes Post-bariatric Surgery | 6 months | 
| Change in Percentage of Lean Mass | Change in percentage of lean body mass as measured by DEXA scan at 6 months compared to randomization | 6 months | 
| Change in Percentage of Truncal Fat | Change in percentage of truncal fat as measured by DEXA scan at 6 months compared to randomization | 6 months | 
| Change in Percentage of Android Fat | Change in percentage of android fat as measured by DEXA scan at 6 months compared to randomization | 6 months | 
| Change in Percentage of Gynoid Fat | Change in percentage of gynoid fat as measured by DEXA scan at 6 months compared to randomization | 6 months | 
| Change in Spine Bone Mineral Density | Change in spine bone marrow density as measured by DEXA scan at 6 months compared to randomization | 6 months | 
| Change in Leg Bone Mineral Density | Change in leg bone marrow density as measured by DEXA scan at 6 months compared to randomization | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-Bariatric Surgery, hemoglobin A1c protein, human