Glargine Versus NPH in Patients With Chronic Kidney Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Type 2 Diabetes Mellitus, Chronic Kidney Disease

Intervention / Treatment
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* Drug: Glargine insulin
* Drug: NPH insulin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glargine insulin<br>This is an open-label, randomized, two-way crossover study , one is IGlar/INPH treatment sequence and, another is INPH/IGlar sequence. Wherein, IGlar refers to glargine insulin and INPH refers to NPH insulin. At the end of the study, all data acquired during the use of insulin glargine, regardless of the sequence were grouped as glargine. | Drug: Glargine insulin<br>* 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<br>* Other names: Lantus insulin ™, Sanofi-Aventis, Brazil;|
| Active Comparator: NPH insulin<br>This is an open-label, randomized, two-way crossover study , one is IGlar/INPH treatment sequence and, another is INPH/IGlar sequence. Wherein, IGlar refers to glargine insulin and INPH refers to NPH insulin. At the end of the study, all data acquired during the use of NPH insulin, regardless of the sequence were grouped as NPH. | Drug: NPH insulin<br>* 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.<br>* Other names: Humulin N™, Lilly, Brazil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in A1c Levels | A1c using high performance liquid chromatography measured in percentage | baseline and 24 weeks | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glargine insulin, Chronic Kidney Disease, CGMS