A Phase 4 interventional study of Glargine insulin and NPH insulin in Type 2 Diabetes Mellitus and Chronic Kidney Disease, sponsored by University of Sao Paulo General Hospital. Completed at 1 site in Brazil. Open to participants aged 40 Years to 80 Years. Per ClinicalTrials.gov, last updated 2017-12-20.
Sponsored by University of Sao Paulo General Hospital · Phase 4, Interventional, and Treatment
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.
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.
3,840 studies on the registry are indexed under Kidney Diseases; 500 are open to participants now.
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Exclusion Criteria:
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
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
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
Also known as: Lantus insulin ™, Sanofi-Aventis, Brazil
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.
Also known as: Humulin N™, Lilly, Brazil
Difference in A1c Levels
A1c using high performance liquid chromatography measured in percentage
Time frame: 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.
Time frame: between 1rst and 24 weeks of each treatment arm
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).
Time frame: 24 week
Total Daily Insulin Dose
Daily total insulin dose at baseline compared to dose at week 24.
Time frame: baseline and 24 weeks
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.
Time frame: baseline and 24 weeks
Serum Creatinine
Creatinine is measured in milligrams per deciliter of blood (mg/dL
Time frame: baseline and 24 weeks
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 /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.
Time frame: baseline and 24 weeks
| Milestone | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin |
|---|---|---|
| Started | 16 | 18 |
| Completed | 14 | 15 |
| Not completed | 2 | 3 |
| Withdrew: Lost to follow-up | 2 | 0 |
| Withdrew: Death | 0 | 1 |
| Withdrew: Adverse event | 0 | 2 |
| Milestone | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin |
|---|---|---|
| Started | 14 | 15 |
| Completed | 14 | 15 |
| Not completed | 0 | 0 |
A1c using high performance liquid chromatography measured in percentage
| percentage | Glargine Insulin Period | NPH Insulin Period |
|---|---|---|
| Baseline | 8.86 ± 1.4 | 8.21 ± 1.3 |
| 24 weeks treatement | 7.95 ± 1.1 | 8.44 ± 1.3 |
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.
| events per patients during 24 weeks | Glargine Insulin Period | NPH Insulin Period |
|---|---|---|
| total hypoglycemic events | 4.87 ± 5.39 | 6.34 ± 9.37 |
| nocturnal hypoglycemias | 0.52 ± 1.03 | 1.52 ± 2.54 |
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).
| percentage of time | Glargine Insulin Period | NPH Insulin Period |
|---|---|---|
| hyperglycemia | 30 ± 19 | 38 ± 19 |
| normoglycemia | 67 ± 19 | 59 ± 19 |
| hypoglycemia | 3 ± 6 | 3 ± 5 |
Daily total insulin dose at baseline compared to dose at week 24.
| units/Kg/day | Glargine Insulin | NPH Insulin |
|---|---|---|
| Baseline | 0.61 ± 0.21 | 0.63 ± 0.21 |
| 24 weeks treatment | 0.64 ± 0.26 | 0.64 ± 0.25 |
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.
| Kg/m² | Glargine Insulin Period | NPH Insulin Period |
|---|---|---|
| Baseline | 29.7 ± 4.7 | 30.0 ± 4.3 |
| 24 weeks treatement | 30.0 ± 4.3 | 30.4 ± 4.7 |
Creatinine is measured in milligrams per deciliter of blood (mg/dL
| mg/dL | Glargine Insulin Period | NPH Insulin Period |
|---|---|---|
| Baseline | 2.4 ± 0.7 | 2.5 ± 1.0 |
| 24 weeks treatement | 2.6 ± 0.8 | 2.6 ± 1.0 |
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.
| ml/min/1.7m² | Glargine Insulin Period | NPH Insulin Period |
|---|---|---|
| Baseline | 28.0 ± 9.6 | 27.4 ± 9.1 |
| 24 weeks treatement | 26.9 ± 10.0 | 25.9 ± 9.7 |
Collected over 1 year. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Glargine Insulin | — | 0/34 (0%) | 0/34 (0%) |
| NPH Insulin | — | 2/34 (5.9%) | 0/34 (0%) |
| Event | Glargine Insulin | NPH Insulin |
|---|---|---|
| Severe hypoglycemiaNervous system disorders | 0/34 | 2/34 |
| Age, Continuous(years) | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin | Total |
|---|---|---|---|
| Mean | 62.8 ± 7.0 | 60.1 ± 8.7 | 61.4 ± 7.9 |
| Sex: Female, Male(Participants) | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin | Total |
|---|---|---|---|
| Female | 4 | 7 | 11 |
| Male | 12 | 11 | 23 |
| Region of Enrollment(participants) | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin | Total |
|---|---|---|---|
| Brazil | 16 | 18 | 34 |
| Duration of Diabetes(years) | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin | Total |
|---|---|---|---|
| Mean | 19.0 ± 11.7 | 19.2 ± 7.0 | 19.1 ± 9.4 |
| Body weight(kg) | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin | Total |
|---|---|---|---|
| Mean | 75.4 ± 11.9 | 82.6 ± 17.4 | 79.2 ± 15.3 |
| BMI(kg/m²) | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin | Total |
|---|---|---|---|
| Mean | 28.6 ± 4.8 | 30.4 ± 4.3 | 29.6 ± 4.6 |
| Systolic Blood Pressure(mmHg) | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin | Total |
|---|---|---|---|
| Mean | 147 ± 22 | 136 ± 18 | 141 ± 20 |
| Diastolic Blood Pressure(mmHg) | Glargine Insulin, Then NPH Insulin | NPH Insulin, Then Glargine Insulin | Total |
|---|---|---|---|
| Mean | 79 ± 12 | 75 ± 13 | 76 ± 12 |
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University of Sao Paulo General Hospital