Prevention and Treatment Of Diabetes Complications With Gastric Surgery or Intensive Medicines

Type 2 Diabetes Clinical Trial

— PRODIGIES  

Official title:

Prevention and Treatment Of Diabetes Complications With Gastric Surgery or Intensive Medicines

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01974544
• Other study ID #: 11-141
• Status: Recruiting
• Phase: N/A
• First received: May 25, 2013
• Last updated: October 27, 2013
• Start date: May 2013
• Est. completion date: December 2016

Study information

• Verified date: October 2013
• Source: Pontificia Universidad Catolica de Chile
• Contact: Castillo Alejandra
• Phone: 56223543257
• Email: macastia[@]uc.cl
• Is FDA regulated: No
• Health authority: Chile: Comisión Nacional de Investigación Científica y Tecnológica
• Study type: Interventional

Clinical Trial Summary

The obesity and type 2 diabetes mellitus (T2DM) are among the most threatening health crisis for the 21st century. Currently, it is estimated that there are 205 million people with T2DM worldwide. Chile has a similar magnitude of problem with the prevalence of diabetes increasing from 6.3% in 2003 to 9.4% in 2010. T2DM is a complex disease characterized by hyperglycemia, insulin resistance and a relative β-cell failure. Well-known studies for the treatment of T2DM (ADVANCE trial) showed that intensive medical treatment significantly reduces the complication of diabetes. On the other hand, less than 40% of patients with T2DM achieve a metabolic control of diabetes, despite medical treatment. Recently, bariatric surgery has emerged as an effective treatment for T2DM. Data from different sources has shown that Roux-en-Y Gastric Bypass (RYGB) can place T2DM into remission. More recently, Sleeve Gastrectomy (SG) has been shown to also impact metabolically and hence also emerged as an attractive T2DM-controlling bariatric procedure with fewer complications than RYGB. Recently, the International Federation for Diabetes has supported the use gastrointestinal surgery initially developed for morbid obesity as an option to treat patients with diabetes. In the current proposal the investigators aim to address several issues concerning metabolic surgery and the ability of the most common bariatric procedures performed to control diabetes. The investigators are proposing a prospective randomized trial comparing RYGB, SG and the best medical treatment availed for the T2DM in poorly control patients with the primary endpoint being 36 month glycemic control (patients achieving HbA1C < 6.5%, normal glucose levels not requiring medication). The main working hypothesis is that RYGB and SG achieves better glycemic control than the best treatment availed for the T2DM based on more effective mechanisms to enhance insulin secretion, insulin sensitivity, lipid metabolism and blood pressure control. The goals are, 1) Is gastric bypass surgery and sleeve gastrectomy safe for the microvascular complications of T2DM?; 2) Can gastric bypass, sleeve gastrectomy surgery and intensive non surgical treatment reverse or reduce the progression of microvascular complications of T2DM?; and 3) Can gastric bypass and sleeve gastrectomy realize a return on investment within 2 years in patients with type 2 diabetes who are at risk of developing or deteriorating microvascular complications?

Description:

Currently 205 million patients in the world suffer with Type 2 diabetes and severe and complex obesity. The obesity is defined as a body mass index above 30 kg/m2 with life or limb threatening co‐morbidities.

The bariatric surgery increase in worldwide, but their effects on the microvascular complications of T2DM have never been the focus of a randomised controlled clinical trial.

To address this research question a three arms on randomised controlled clinical trial comparing gastric bypass surgery, sleeve gastrectomy and modern best medical care is required to investigate differences in long term glycaemia and microvascular complications of T2DM.

This is a prospective intervention study on patients with T2DM and obesity undergoing gastric bypass surgery, sleeve gastrectomy or non surgical best medical care. Patients will have T2DM for more than 2 years and have or be at high risk of developing kidney damage. Patients will be recruited from specialist medical and surgical clinics.

We expect to screen approximately 300 patients to allow 75 to be randomized. Twenty five subjects with kidney damage or high risk of kidney damage secondary to T2DM will undergo gastric bypass surgery. Another 25 sleeve gastrectomy and the final 25 will be treated using the American Diabetes Association protocol. Patients with HbA1c ≥9.0% will undergo individualised optimisation of glycaemia as this should improve surgical outcomes. Particular attention will be given to the avoidance of hypoglycaemia. Patients' other risk factors (including hypertension and dyslipidaemia) will be optimised based on the International Diabetes Federation guidelines.

The clinical endpoints that will be assessed are: renal function, peripheral and autonomic nervous system function, the retina, of direct healthcare cost, glycaemic control, blood pressure, lipids, quality of life, postprandial responses, treatment complications.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: December 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Type 2 diabetes with HbA1c > 7%

2. Duration of diabetes of more than 2 years

3. The glomerular filtration rate (GFR) > 30 ml/min per 1.73 m2

4. BMI < 35 kg/m2

5. Age 18-65

6. Established microalbuminuria or at high risk of microalbuminuria

Exclusion Criteria:

1. Type 1 diabetes or positive Glutamic acid decarboxylase antibodies (Anti-GAD)

2. BMI >35 kg/m2

3. End stage retinopathy, nephropathy or neuropathy (defined as high risk/advanced proliferative retinopathy on the Early Treatment Diabetic Retinopathy Study Severity Scale or blindness, Stage 5 chronic kidney disease, patients requiring dialysis or transplantation, Stage 3 peripheral neuropathy)

4. Unacceptably high risk for general anaesthesia.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Complications
• Type 2 Diabetes

Intervention

Drug:
• Best medical treatment
If patients are unable to maintain their haemoglobin A1c (HbA1c) values below 6.5% on diet alone, treatment with metformin 1g twice daily will be started. If HbA1c remains above 7.0% then liraglutide 0.6 mg once daily (with a subsequent increases to 1.2 mg and 1.8 mg once daily). If liraglutide is not tolerated then a Dipeptidyl peptidase IV inhibitor (sitagliptin, saxagliptin, linagliptin) or pioglitazone will be considered. If HbA1c remains above 7.5% long acting insulin analogues such as detemir o glargine will be added. If insulin is started liraglutide can be stopped. The insulin dose will be adjusted according to the morning fasting blood glucose concentration. Finally, Fast-acting meal time insulin (lispro, aspart or glulisine) will be added if glycemic goal is not achieved. Repaglinide can be considered in patients with significant renal impairment and in patients who refused insulin treatment.

Procedure:
• gastric bypass
For the gastric bypass, the gastric pouch will be adjusted to a volume of 15-20 ml. The alimentary limb will be a standard 150 cm and the biliopancreatic limb 50 cm. A hand-sewn gastro-jejunal anastomosis will be performed over a 34 French bougie
• sleeve gastrectomy
The sleeve gastrectomy will be done using laparoscopic staplers over a 34 French bougie.The greater curvature will be dissected 4 cm proximal to the pylorus leaving the antrum. Short gastric vessels will be dissected using the harmonic scalpel up to the gastro-esophageal junction. The stapler will be reinforced. The resected stomach will be removed in a plastic bag through the left flank trocar

Drug:
• General interventions for all groups: blood presure
Patients will receive an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin II receptor antagonists (ARA II) to meet strict blood pressure targets of the ADA / European Association for Study of Diabetes (EASD) or in the presence of micro or macroalbuminuria. In addition to ACE inhibitors (or if there were side-effects, an angiotensin-II receptor antagonist), calcium antagonist, diuretics or Beta blockers can be added as needed. Aspirin 100 mg daily will be used for secondary prevention in patients with a history of ischaemic cardiovascular disease.
• General interventions for all groups: dysilipidemia
Raised fasting serum cholesterol concentrations (greater than 4.5 mmol/L) or combined dyslipidaemias will be treated with atorvastatin 10-80mg once daily. Gemfibrozilo or fenofibrate once daily can be used for isolated hypertriglyceridaemia (fasting serum triglyceride concentration >4.0 mmol/L), or fenofibrate can be added to statin treatment if the fasting serum triglyceride concentration was also raised (>4.0 mmol/L).

Behavioral:
• General interventions for all groups: lifestyle
Exercise is an important part of the diabetes management plan. The ADA recommendations for the adults with diabetes is at least 150 min/week of moderate-intensity aerobic physical activity (50-70% of maximum heart rate), with no more than two consecutive days without exercise. A kinesiologist will design an individual plan of physical training for each patient. Also, a nutritionist will be design an individual dietitian plan, this plan should be formulated as a collaborative therapeutic alliance among the patient and family, physician, and other members of the health care team.

Locations

Country	Name	City	State
Chile	Pontificia Universidad Católica de Chile	Santiago	Región Metropolitana

Sponsors (1)

Lead Sponsor	Collaborator
Pontificia Universidad Catolica de Chile

Country where clinical trial is conducted

Chile, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the microvascular complications of type 2 diabetes, specifically diabetic kidney disease	These outcome will be measured through the glomerular filtration rate (GFR), (MDRD-1 equation: GFR (expressed in ml/min/1.73 m2), and Albuminuria (ACR (mg/g).	baseline at 1 month before the intervention and 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 month after intervention	No
Primary	Change in the microvascular complications of type 2 diabetes, specifically Retinopathy.	This will be measured through assessment by ophthalmologist.	baseline at 1 month before the intervention, 12 y 24 month after intervention	No
Primary	Change in the microvascular complications of type 2 diabetes, specifically peripheral and sympathic neuropathy.	This will be measured through assessment nerve conduction, sensory nerve conduction, motor nerve conduction, sympathic skin response.	baseline at 1 month before the intervention, 12, 24 y 36 month	No
Secondary	Assessment of the optimization of the metabolic control, defined by the International Diabetes Federation	This will be measured through haemoglobin A1c (HbA1c) (%), continuous glucose monitoring, blood pressure (mmhg), total cholesterol (mg/dL), HDL (mg/dL), LDL (mg/dL), triglycerides (mg/dL).	baseline at 1 month before the intervention and 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 month after the intervention	No
Secondary	Assessment of treatment complications	This will be measured through the record of all treatment complications like: Infection or surgical bleeding, inflammation of the veins for drug administration, temporary digestive disorders, gastroesophageal reflux disease, or acute retention of urine infection, prolonged pain in the area of operation. Specifically for the Gastric Bypass, intestinal fistulas poor healing of sutures, nutritional deficiencies, excessive weight loss. Less often marginal ulcerative lesions and intestinal obstruction. In the other side, the sleeve gastrectomy: dehiscence of the suture line and nutritional complications.	1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 month after intervention	No
Secondary	Assessment of the quality of life.	This will be measured through the Diabetes Quality of Life Questionnaire.	baseline at 1 month before the intervention and 3, 6, 12, and 24 month after the intervention	No
Secondary	Assessment of macrovascular events	This will be measured through the record of all macrovascular events, like cardiovascular deaths, nonfatal myocardial infarction, cardiovascular interventions, nonfatal stroke, amputation or surgery for peripheral atherosclerotic artery disease.	baseline at 1 month before the intervention and 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 month after the intervention	No
Secondary	How many patients not requiring antidiabetic agents	This will be measured through the record of number of patient who requiring oral antidiabetic agent, number of patient who requiring insulin, and both.	baseline 1 month after intervention, and at 6, 12, 18, 24, 30, and 36 month after intervention	No