Type 2 Diabetes MellitusPhase 4NCT02451917
Glargine Versus NPH in Patients With Chronic Kidney Disease
A Phase 4 study testing Glargine insulin and NPH insulin in people with Type 2 Diabetes Mellitus and Chronic Kidney Disease, run by University of Sao Paulo General Hospital at 1 site in Brazil.
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. Read more about this study
- Who is it for?
- Ages 40 to 80 years
- Conditions the study is for
- Type 2 Diabetes Mellitus, Chronic Kidney Disease
- What is being tested?
- Glargine insulin and NPH insulin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteBrazil
- Study dates
- Dec 2013to Aug 2016
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- Patients with systemic neoplasias,
- HIV, chronic kidney disease or nephropathy from other etiologies,
- severe psychiatric disorders
- pregnant women.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Subcutaneous Insulin Glargine Versus NPH Insulin in Patients With Chronic Kidney Disease Stages III and IV: Randomized Controlled Trial.
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.
Read the 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.
- Conditions
- Type 2 Diabetes Mellitus, Chronic Kidney Disease
- Being tested
- Glargine insulin, NPH insulin
- Keywords
- Glargine insulin, Chronic Kidney Disease, CGMS
- Medical subject headings
- Diabetes Mellitus, Type 2, Renal Insufficiency, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Glargine insulinDrug
Also called Lantus insulin ™, Sanofi-Aventis, Brazil
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 insulinDrug
Also called Humulin N™, Lilly, 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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: NPH insulin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Difference in A1c Levels
A1c using high performance liquid chromatography measured in percentage
Measured: 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.
Measured: between 1rst and 24 weeks of each treatment arm
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2015 (estimated)
- Study startDec 2013
- Primary completionAug 2016
- Study completionAug 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Type 2 Diabetes MellitusStudies of the same condition, open and under way.
- More trials run by University of Sao Paulo General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Marcia S Queiroz, MD, PhD, Principal investigator, Assistant Professor at Division of Endocrinology and Metabolism, Department of Internal Medicine, Clinic Hospital of the University of São Paulo Medical School
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02451917
- Sponsor's protocol ID
- ENDONEFRO
- Status last verified
- Aug 2016
- First submitted
- 25 Aug 2014
- Last updated
- 20 Dec 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 33166419Betonico 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.
PubMed 31383366
Study at a glance
From the registry record, last updated by the sponsor on 20 Dec 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Subcutaneous Insulin Glargine Versus NPH Insulin in Patients With Chronic Kidney Disease Stages III and IV: Randomized Controlled Trial.
- ClinicalTrials.gov ID
- NCT02451917
- Acronym / sponsor ID
- ENDONEFRO
- Conditions
- Type 2 Diabetes Mellitus, Chronic Kidney Disease
- Keywords
- Glargine insulin, Chronic Kidney Disease, CGMS
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- University of Sao Paulo General HospitalUniversity, hospital or other
- Study start
- Dec 2013
- Primary completion
- Aug 2016 (actual)
- Study completion
- Aug 2016 (actual)
- First posted
- 22 May 2015 (estimated)
- Results
- Posted 7 Nov 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Glargine insulin | Experimental | Drug: Glargine insulinThis 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. |
| NPH insulin | Active comparator | Drug: NPH insulinThis 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. |
Who may qualify
- Ages
- 40 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (4 listed)
- Patients with systemic neoplasias,
- HIV, chronic kidney disease or nephropathy from other etiologies,
- severe psychiatric disorders
- pregnant women.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Glargine insulinAlso: Lantus insulin ™, Sanofi-Aventis, BrazilThe 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 | Drug | Glargine insulin |
| NPH insulinAlso: Humulin N™, Lilly, BrazilThe 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. | Drug | NPH insulin |
Primary outcome
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Dec 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33166419Semlitsch 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.
- Derived from this study: PubMed 31383366Betonico 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marcia S Queiroz, MD, PhD principal investigator
Assistant Professor at Division of Endocrinology and Metabolism, Department of Internal Medicine, Clinic Hospital of the University of São Paulo Medical School
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Glargine insulin and NPH insulin in people with Type 2 Diabetes Mellitus and Chronic Kidney Disease, run by University of Sao Paulo General Hospital at 1 site in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Nov 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in A1c Levels (time frame: baseline and 24 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02451917, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Dec 2017.