Trial Outcomes & Findings for Glargine Versus NPH in Patients With Chronic Kidney Disease (NCT NCT02451917)

NCT ID: NCT02451917

Last Updated: 2017-12-20

Results Overview

A1c using high performance liquid chromatography measured in percentage

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 34 participants
• Primary outcome timeframe: baseline and 24 weeks
• Results posted on: 2017-12-20

Participant Flow

Participant milestones

Measure	Glargine Insulin, Then 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	NPH Insulin, Then Glargine 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.
First Intervention (24 Weeks) STARTED	16	18
First Intervention (24 Weeks) COMPLETED	14	15
First Intervention (24 Weeks) NOT COMPLETED	2	3
Second Intervention (24 Weeks) STARTED	14	15
Second Intervention (24 Weeks) COMPLETED	14	15
Second Intervention (24 Weeks) NOT COMPLETED	0	0

Reasons for withdrawal

Measure	Glargine Insulin, Then 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	NPH Insulin, Then Glargine 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.
First Intervention (24 Weeks) Lost to Follow-up	2	0
First Intervention (24 Weeks) Death	0	1
First Intervention (24 Weeks) Adverse Event	0	2

Baseline Characteristics

Glargine Versus NPH in Patients With Chronic Kidney Disease

Baseline characteristics by cohort

Measure	Glargine Insulin, Then NPH Insulin n=16 Participants 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 Insulin, Then Glargine Insulin n=18 Participants 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.	Total n=34 Participants Total of all reporting groups
Age, Continuous	62.8 years STANDARD_DEVIATION 7.0 • n=5 Participants	60.1 years STANDARD_DEVIATION 8.7 • n=7 Participants	61.4 years STANDARD_DEVIATION 7.9 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	7 Participants n=7 Participants	11 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	11 Participants n=7 Participants	23 Participants n=5 Participants
Region of Enrollment Brazil	16 participants n=5 Participants	18 participants n=7 Participants	34 participants n=5 Participants
Duration of Diabetes	19.0 years STANDARD_DEVIATION 11.7 • n=5 Participants	19.2 years STANDARD_DEVIATION 7.0 • n=7 Participants	19.1 years STANDARD_DEVIATION 9.4 • n=5 Participants
Body weight	75.4 kg STANDARD_DEVIATION 11.9 • n=5 Participants	82.6 kg STANDARD_DEVIATION 17.4 • n=7 Participants	79.2 kg STANDARD_DEVIATION 15.3 • n=5 Participants
BMI	28.6 kg/m² STANDARD_DEVIATION 4.8 • n=5 Participants	30.4 kg/m² STANDARD_DEVIATION 4.3 • n=7 Participants	29.6 kg/m² STANDARD_DEVIATION 4.6 • n=5 Participants
Systolic Blood Pressure	147 mmHg STANDARD_DEVIATION 22 • n=5 Participants	136 mmHg STANDARD_DEVIATION 18 • n=7 Participants	141 mmHg STANDARD_DEVIATION 20 • n=5 Participants
Diastolic Blood Pressure	79 mmHg STANDARD_DEVIATION 12 • n=5 Participants	75 mmHg STANDARD_DEVIATION 13 • n=7 Participants	76 mmHg STANDARD_DEVIATION 12 • n=5 Participants

PRIMARY outcome

Timeframe: baseline and 24 weeks

Population: Primary endpoint A1c was assessed using an analysis of covariance (ANOVA) model.

A1c using high performance liquid chromatography measured in percentage

Outcome measures

Measure	Glargine Insulin Period n=34 Participants 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 insulin.	NPH Insulin Period n=34 Participants 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 insulin.
Difference in A1c Levels Baseline	8.86 percentage Standard Deviation 1.4	8.21 percentage Standard Deviation 1.3
Difference in A1c Levels 24 weeks treatement	7.95 percentage Standard Deviation 1.1	8.44 percentage Standard Deviation 1.3

PRIMARY outcome

Timeframe: between 1rst and 24 weeks of each treatment arm

Population: Endpoint hypoglycemia was assessed using an analysis of covariance (ANOVA) model

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.

Outcome measures

Measure	Glargine Insulin Period n=34 Participants 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 insulin.	NPH Insulin Period n=34 Participants 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 insulin.
Number of Hypoglycemic Events total hypoglycemic events	4.87 events per patients during 24 weeks Standard Deviation 5.39	6.34 events per patients during 24 weeks Standard Deviation 9.37
Number of Hypoglycemic Events nocturnal hypoglycemias	0.52 events per patients during 24 weeks Standard Deviation 1.03	1.52 events per patients during 24 weeks Standard Deviation 2.54

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 week

Population: Patients were excluded from the analysis because of unfamiliarity with mechanical procedures related to the CGM use, visual impairment or technical problems with the sensor measurement.

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).

Outcome measures

Measure	Glargine Insulin Period n=24 Participants 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 insulin.	NPH Insulin Period n=24 Participants 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 insulin.
Glycemic Variability hyperglycemia	30 percentage of time Standard Deviation 19	38 percentage of time Standard Deviation 19
Glycemic Variability normoglycemia	67 percentage of time Standard Deviation 19	59 percentage of time Standard Deviation 19
Glycemic Variability hypoglycemia	3 percentage of time Standard Deviation 6	3 percentage of time Standard Deviation 5

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline and 24 weeks

Population: Randomization was stratified by the A1c value at baseline: \<9.0% or ≥9.0%, in a 1:1 ratio, and the individuals who met all inclusion-criteria were allocated alternately to either an IGlar/INPH or an INPH/IGlar treatment sequence.

Daily total insulin dose at baseline compared to dose at week 24.

Outcome measures

Measure	Glargine Insulin Period n=34 Participants 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 insulin.	NPH Insulin Period n=34 Participants 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 insulin.
Total Daily Insulin Dose Baseline	0.61 units/Kg/day Standard Deviation 0.21	0.63 units/Kg/day Standard Deviation 0.21
Total Daily Insulin Dose 24 weeks treatment	0.64 units/Kg/day Standard Deviation 0.26	0.64 units/Kg/day Standard Deviation 0.25

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline and 24 weeks

Population: BMI endpoint was assessed using an analysis of covariance (ANOVA) model.

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.

Outcome measures

Measure	Glargine Insulin Period n=34 Participants 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 insulin.	NPH Insulin Period n=34 Participants 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 insulin.
Body Mass Index (BMI) Baseline	29.7 Kg/m² Standard Deviation 4.7	30.0 Kg/m² Standard Deviation 4.3
Body Mass Index (BMI) 24 weeks treatement	30.0 Kg/m² Standard Deviation 4.3	30.4 Kg/m² Standard Deviation 4.7

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline and 24 weeks

Population: Creatinine endpoint was assessed using an analysis of covariance (ANOVA) model.

Creatinine is measured in milligrams per deciliter of blood (mg/dL

Outcome measures

Measure	Glargine Insulin Period n=34 Participants 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 insulin.	NPH Insulin Period n=34 Participants 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 insulin.
Serum Creatinine Baseline	2.4 mg/dL Standard Deviation 0.7	2.5 mg/dL Standard Deviation 1.0
Serum Creatinine 24 weeks treatement	2.6 mg/dL Standard Deviation 0.8	2.6 mg/dL Standard Deviation 1.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	Glargine Insulin Period n=34 Participants 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 insulin.	NPH Insulin Period n=34 Participants 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 insulin.
Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI Baseline	28.0 ml/min/1.7m² Standard Deviation 9.6	27.4 ml/min/1.7m² Standard Deviation 9.1
Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI 24 weeks treatement	26.9 ml/min/1.7m² Standard Deviation 10.0	25.9 ml/min/1.7m² Standard Deviation 9.7

Adverse Events

Glargine Insulin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

NPH Insulin

Serious events: 2 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Glargine Insulin n=34 participants at risk 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. 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	NPH Insulin n=34 participants at risk 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. 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.
Nervous system disorders Severe hypoglycemia	0.00% 0/34 • 1 year 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.	5.9% 2/34 • Number of events 2 • 1 year 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.

Other adverse events

Adverse event data not reported

Additional Information

Marcia Silva Queiroz, MD, PhD

Endocrinology Division, University of São Paulo Medical School,

Phone: + 5511 26616293

Email: marcia.queiroz@hc.fm.usp.br

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place