Glargine Versus NPH in Patients With Chronic Kidney Disease

Type 2 Diabetes Mellitus Clinical Trial

Official title:

Subcutaneous Insulin Glargine Versus NPH Insulin in Patients With Chronic Kidney Disease Stages III and IV: Randomized Controlled Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02451917
• Other study ID #: ENDONEFRO
• Status: Completed
• Phase: Phase 4
• First received: August 25, 2014
• Last updated: November 22, 2017
• Start date: December 2013
• Est. completion date: August 2016

Study information

• Verified date: August 2016
• Source: University of Sao Paulo General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Chronic kidney disease (CKD) is one of the most common microvascular complications of diabetes mellitus, and it is the leading cause of end stage renal disease on developed countries. The CKD diagnosis and its progression require re-evaluation of hypoglycemic therapy and constant dosing adjustments, in order to optimize glycemic control and minimize its side effects. Long acting insulin analogs and its pharmacokinetics have not been studied through different stages of kidney disease and there is no consensus defining the appropriate dosing adjustment based on the glomerular filtration rate (GFR). This research project will compare the glycemic response to intensive insulin treatment with NPH insulin and basal insulin analog (insulin glargine) in type 2 diabetes (DM 2) patients with CKD stages 3 and 4. Patients and methods - Inclusion Criteria: DM 2 patients with CKD secondary to diabetic nephropathy and GFR of 15-59 ml/min/1.73m². Exclusion Criteria: Patients with systemic neoplasia, HIV, CKD or nephropathy from other etiologies, severe psychiatric disorders and pregnant women. Study design: This study consists of a randomized, cross-over, open-label controlled clinical trial. Patients will be randomly divided into two groups: GROUP 1 - insulin analog glargine once a day and GROUP 2 - NPH human insulin, three applications per day, both group will be treated with insulin lispro at mealtime. The laboratory tests will be performed at baseline and 12, 24, 36 and 48 weeks after the study start. During routine medical appointments will be analyzed self- monitoring of capillary blood glucose (SMBG) and the hypoglycemia score. After 24 weeks the basal insulin will be changed, i.e. patients using NPH insulin will receive insulin glargine and patients on insulin glargine will be changed to NPH insulin. A CGMS will be carried out at 24 and 48 weeks. Methodology: The metabolic profile will be evaluated throughout SMBG; biochemical, hormonal and hematological measurements; hypoglycemia score and CGMS. Statistical analysis will be performed using comparative descriptive analyzes, such as chi-square distribution, t-test and non-parametric tests. Analyze of data CGMS will include the area under the curve and the related statistic. Finally, logistic regression models will be adopted to evaluate the effect of the treatment on the several variables in question.

Description:

This study consists of a randomized, cross-over, open-label controlled clinical trial. Randomized patients will be allocated alternately into two groups to receive the following therapies: GROUP 1 - insulin analog glargine once a day associated to insulin lispro at mealtime and GROUP 2 - NPH human insulin, three applications per day ( breakfast, lunch and bedtime) and insulin lispro at mealtime. Patients receiving insulin NPH plus insulin lispro will be oriented to mix both of them in the same syringe at breakfast and lunchtime. The laboratory tests will be performed at baseline and 12, 24, 36 and 48 weeks after the study start. During routine medical appointments the patient should bring the self- monitoring of capillary blood glucose (SMBG), eight points per day once a week, and hypoglycemia score.

After 24 weeks of insulin therapy, a continuous glucose monitoring system (CGMS) will be implemented for three days, and after that, the basal insulin changed i.e. patients using NPH insulin will receive insulin glargine and patients on insulin glargine will be changed to NPH insulin, both groups will keep insulin lispro before meals. A new CGMS will be carried out 24 weeks after therapy has been changed. Methodology: The metabolic profile will be evaluated throughout SMBG; biochemical, hormonal and hematological measurements; hypoglycemia score and CGMS (Medtronic/Northridge, CA). All randomized patients who use at least one dose of any study treatment will be considered in the Intent-to-treat (ITT) population. The initial plan is to randomize 40 patients, assuming a drop-out rate of 15%, to obtain a sample size of at least 34 randomized patients. .Statistical analysis will be performed using comparative descriptive analyzes, such as chi-square distribution, t-test and non-parametric tests. Analyze of data CGMS will include the area under the curve and the related statistic. Finally, logistic regression models will be adopted to evaluate the effect of the treatment on the several variables in question.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: August 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

• Patients with type 2 diabetes mellitus and chronic kidney disease secondary to diabetic nephropathy in stages 3 and 4 (moderate and severe nephropathy, corresponding to glomerular filtration rate of 15-59 ml/min/1.73m²) will be included in the study.

Exclusion Criteria:

• Patients with systemic neoplasias,

• HIV, chronic kidney disease or nephropathy from other etiologies,

• severe psychiatric disorders

• pregnant women.

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Kidney Diseases
• Renal Insufficiency, Chronic
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Glargine insulin
The initial insulin dose for those randomized to IGlar was 80% of the total daily NPH dose that was being discontinued. All of them had pre-prandial Regular insulin switched to Lispro insulin (Humalog™, Lilly, Brazil), at the same dose as in use previously. After 24 weeks, basal insulins were switched; in other words, individuals on IGlar in the first period switched to INPH, and the doses of pre-meal insulin were sustained
• NPH insulin
The same total daily NPH insulin dose was maintained for those randomized to INPH. All of them had pre-prandial Regular insulin (Humulin R™, Lilly, Brazil) switched to Lispro insulin (Humalog™, Lilly, Brazil), at the same dose as in use previously. . After 24 weeks, basal insulins were switched; in other words, individuals on NPH in the first period switched to glargine insulin, and the doses of pre-meal insulin were sustained.

Locations

Country	Name	City	State
Brazil	University of Sao Paulo	Sao Paulo

Sponsors (1)

Lead Sponsor	Collaborator
University of Sao Paulo General Hospital

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Glycemic Variability	In order to observe variability in interstitial glucose levels related to the therapy in use, participants wore a blinded CGM for 3 days. Changes in glycemic patterns were expressed by the average daily time spent in hypoglycemia (=70 mg/dL or <3.9 mmol/L), hyperglycemia (>180 mg/dL or >10 mmol/L) and euglycemia (70-180 mg/dL or 3.9-10 mmol/L).	24 week
Other	Total Daily Insulin Dose	Daily total insulin dose at baseline compared to dose at week 24.	baseline and 24 weeks
Other	Body Mass Index (BMI)	The BMI is defined as the body mass divided by the square of the body height, and is universally expressed in units of kg/m2, resulting from mass in kilograms and height in metres.	baseline and 24 weeks
Other	Serum Creatinine	Creatinine is measured in milligrams per deciliter of blood (mg/dL	baseline and 24 weeks
Other	Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI	Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is one of the most widely used IDMS traceable equations for estimating GFR in patients age 18 and over. CKD-EPI equation includes variables for age, gender, and race, which may allow providers to observe that CKD is present despite a serum creatinine concentration that appears to fall within or just above the normal reference interval.; CKD-EPI equation expressed as a single equation: GFR = 141 × min (Scr /?, 1)a × max(Scr /?, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where: Scr is serum creatinine in mg/dL, ? is 0.7 for females and 0.9 for males, a is -0.329 for females and -0.411 for males,min indicates the minimum of Scr /? or 1, and max indicates the maximum of Scr /? or 1.	baseline and 24 weeks
Primary	Difference in A1c Levels	A1c using high performance liquid chromatography measured in percentage	baseline and 24 weeks
Primary	Number of Hypoglycemic Events	Hypoglycemia was defined by capillary glycemia< 70 mg/dL (3.9 mmol/L), even if it was not accompanied by typical symptoms. Otherwise, hypoglycemia was classified as "severe" with SMBG below 50 mg/dL (2.8 mmol/L) or when it resulted in stupor, seizure, or unconsciousness that precluded self-treatment, thus requiring the assistance of another individual. Nocturnal events were defined as SMBG < 70mg/dL occurring after midnight and before wake-up in the morning (before 7:00am)12.	between 1rst and 24 weeks of each treatment arm