Glargine Versus NPH in Patients With Chronic Kidney Disease

NCT02451917 | Completed Phase 4 Results DMC

• 1 other identifier: ENDONEFRO
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes Mellitus; Chronic Kidney Disease

Keywords

Glargine insulin; Chronic Kidney Disease; CGMS

Outcome Measures

Primary Outcomes (2)

• 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

Other Outcomes (5)

• Glycemic Variability

  24 week

• Total Daily Insulin Dose

  baseline and 24 weeks

• Body Mass Index (BMI)

  baseline and 24 weeks

Study Arms (2)

Glargine insulin

EXPERIMENTAL

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

NPH insulin

ACTIVE COMPARATOR

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

Interventions

Glargine insulin DRUG

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

Glargine insulin

NPH insulin DRUG

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

NPH insulin

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Patients with systemic neoplasias,
• HIV, chronic kidney disease or nephropathy from other etiologies,
• severe psychiatric disorders
• pregnant women.

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead

Study Sites (1)

University of Sao Paulo

São Paulo, 05410001, Brazil

Location

Related Publications (2)

• Semlitsch T, Engler J, Siebenhofer A, Jeitler K, Berghold A, Horvath K. (Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 9;11(11):CD005613. doi: 10.1002/14651858.CD005613.pub4.

  PMID: 33166419 DERIVED

• Betonico 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.

  PMID: 31383366 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Renal Insufficiency, Chronic

Interventions

Insulin Glargine; Insulin, Isophane; Isophane Insulin, Human

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Insulin, Long-Acting; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Insulin, Regular, Human; Insulin; Proinsulin

Limitations and Caveats

The results only apply to patients with T2DM and DKD stages 3 and 4 and do not allow us to extrapolate any conclusion to those on dialysis or initial stages of DKD. The patients were randomized alternately, in accordance with the initial A1c.

Results Point of Contact

• Title: Marcia Silva Queiroz, MD, PhD
• Organization: Endocrinology Division, University of São Paulo Medical School,

marcia.queiroz@hc.fm.usp.br

+ 5511 26616293

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2014
• First Posted: May 22, 2015
• Study Start: December 1, 2013
• Primary Completion: August 1, 2016
• Study Completion: August 1, 2016
• Last Updated: December 20, 2017
• Results First Posted: November 7, 2017

Record last verified: 2016-08

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)