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Glargine Versus NPH in Patients With Chronic Kidney Disease

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ClinicalTrials.gov Identifier: NCT02451917
Recruitment Status : Completed
First Posted : May 22, 2015
Results First Posted : November 7, 2017
Last Update Posted : December 20, 2017
Sponsor:
Information provided by (Responsible Party):
University of Sao Paulo General Hospital

Tracking Information
First Submitted Date  ICMJE August 25, 2014
First Posted Date  ICMJE May 22, 2015
Results First Submitted Date  ICMJE October 20, 2016
Results First Posted Date  ICMJE November 7, 2017
Last Update Posted Date December 20, 2017
Study Start Date  ICMJE December 2013
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 31, 2017)
  • Difference in A1c Levels [ Time Frame: baseline and 24 weeks ]
    A1c using high performance liquid chromatography measured in percentage
  • Number of Hypoglycemic Events [ Time Frame: between 1rst and 24 weeks of each treatment arm ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 21, 2015)
Change in Glycated Hemoglobin (A1c) [ Time Frame: baseline, 6 and 12 months ]
Change History Complete list of historical versions of study NCT02451917 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2015)
hypoglycemia [ Time Frame: 12 months ]
number of hypoglycemic events graduated by specific score
Current Other Pre-specified Outcome Measures
 (submitted: November 22, 2017)
  • Glycemic Variability [ Time Frame: 24 week ]
    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).
  • Total Daily Insulin Dose [ Time Frame: baseline and 24 weeks ]
    Daily total insulin dose at baseline compared to dose at week 24.
  • Body Mass Index (BMI) [ Time Frame: baseline and 24 weeks ]
    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.
  • Serum Creatinine [ Time Frame: baseline and 24 weeks ]
    Creatinine is measured in milligrams per deciliter of blood (mg/dL
  • Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI [ Time Frame: baseline and 24 weeks ]
    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 /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where: Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males,min indicates the minimum of Scr /κ or 1, and max indicates the maximum of Scr /κ or 1.
Original Other Pre-specified Outcome Measures
 (submitted: May 21, 2015)
  • glycemic variability [ Time Frame: 6 and 12 months ]
    Analyze CGMS data based on standard deviations (SDS) and related methods (percent coefficient of variation [CV%] and interquartile range [IQR])
  • Total Daily Insulin Dose [ Time Frame: baseline, 6 and 12 monts ]
    Represents all insulin doses prescribed by day, calculated by sum basal and prandial insulin
  • Number of admission to program renal replacement therapy (dialysis or transplantation), hospitalizations and deaths . [ Time Frame: 6 and 12 months ]
  • creatinine slope [ Time Frame: 6 and 12 months ]
    Laboratorial dosage of creatinine at 6 and 12 months compare to baseline dosage
  • glomerular filtration rate [ Time Frame: 6 and 12 months ]
    calculated based on mathematical formulas as Krocoft-Gault and MDRD and compare to baseline
 
Descriptive Information
Brief Title  ICMJE Glargine Versus NPH in Patients With Chronic Kidney Disease
Official Title  ICMJE Subcutaneous Insulin Glargine Versus NPH Insulin in Patients With Chronic Kidney Disease Stages III and IV: Randomized Controlled Trial.
Brief 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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 2 Diabetes Mellitus
  • Chronic Kidney Disease
Intervention  ICMJE
  • 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
    Other Name: Lantus insulin ™, Sanofi-Aventis, Brazil
  • Drug: 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.
    Other Name: Humulin N™, Lilly, Brazil
Study Arms  ICMJE
  • Experimental: Glargine insulin
    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.
    Intervention: Drug: Glargine insulin
  • Active Comparator: NPH insulin

    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.

    Intervention: Drug: NPH insulin
Publications * Betônico CC, Titan SMO, Lira A, Pelaes TS, Correa-Giannella MLC, Nery M, Queiroz M. Insulin Glargine U100 Improved Glycemic Control and Reduced Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3 and 4. Clin Ther. 2019 Oct;41(10):2008-2020.e3. doi: 10.1016/j.clinthera.2019.07.011. Epub 2019 Aug 2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 31, 2017)
34
Original Estimated Enrollment  ICMJE
 (submitted: May 21, 2015)
30
Actual Study Completion Date  ICMJE August 2016
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02451917
Other Study ID Numbers  ICMJE ENDONEFRO
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Sao Paulo General Hospital
Study Sponsor  ICMJE University of Sao Paulo General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Marcia S Queiroz, MD, PhD Assistant Professor at Division of Endocrinology and Metabolism, Department of Internal Medicine, Clinic Hospital of the University of São Paulo Medical School
PRS Account University of Sao Paulo General Hospital
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP