Trial Outcomes & Findings for Comparison of the Blood Sugar Lowering Effect and Safety of Two Insulin Treatments in Type 2 Diabetes (NCT NCT00537303)

NCT ID: NCT00537303

Last Updated: 2017-03-10

Results Overview

Analysed for the full analysis set.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 296 participants
• Primary outcome timeframe: week 36
• Results posted on: 2017-03-10

Participant Flow

A total of 67 centres in 12 countries participated: Denmark (1), Finland (6), France (5), Netherlands (6), Norway (5), Russian Federation (4), Serbia (2), South Africa (3), Spain (5), Sweden (3), United Kingdom (7), United States of America (20)

Eligible subjects were included in a 12-weeks forced titration period with insulin detemir as add-on to current oral anti-diabetic drug (OAD) treatment. Those subjects who did not meet the HbA1c target below 7% were then randomised to one of the two treatment regimens. Any use of sulphonylurea was discontinued at the time of randomisation.

Participant milestones

Measure	Advanced Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Overall Study STARTED	146	150
Overall Study COMPLETED	120	125
Overall Study NOT COMPLETED	26	25

Reasons for withdrawal

Measure	Advanced Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Overall Study Adverse Event	1	4
Overall Study Lack of Efficacy	6	7
Overall Study Protocol Violation	8	4
Overall Study Withdrawal criteria	3	3
Overall Study Unclassified	8	7

Baseline Characteristics

Comparison of the Blood Sugar Lowering Effect and Safety of Two Insulin Treatments in Type 2 Diabetes

Baseline characteristics by cohort

Measure	Advanced n=146 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=150 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Total n=296 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	117 Participants n=5 Participants	122 Participants n=7 Participants	239 Participants n=5 Participants
Age, Categorical >=65 years	29 Participants n=5 Participants	28 Participants n=7 Participants	57 Participants n=5 Participants
Age, Continuous	58.3 years STANDARD_DEVIATION 8.29 • n=5 Participants	58.3 years STANDARD_DEVIATION 8.54 • n=7 Participants	58.3 years STANDARD_DEVIATION 8.40 • n=5 Participants
Sex: Female, Male Female	70 Participants n=5 Participants	67 Participants n=7 Participants	137 Participants n=5 Participants
Sex: Female, Male Male	76 Participants n=5 Participants	83 Participants n=7 Participants	159 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	26 Participants n=5 Participants	34 Participants n=7 Participants	60 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	108 Participants n=5 Participants	103 Participants n=7 Participants	211 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	12 Participants n=5 Participants	13 Participants n=7 Participants	25 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) White	120 Participants n=5 Participants	122 Participants n=7 Participants	242 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	12 Participants n=5 Participants	13 Participants n=7 Participants	25 Participants n=5 Participants
Height	1.68 meter STANDARD_DEVIATION 0.10 • n=5 Participants	1.67 meter STANDARD_DEVIATION 0.10 • n=7 Participants	1.68 meter STANDARD_DEVIATION 0.10 • n=5 Participants
Body weight	88.8 kg STANDARD_DEVIATION 15.8 • n=5 Participants	88.0 kg STANDARD_DEVIATION 16.3 • n=7 Participants	88.4 kg STANDARD_DEVIATION 16.0 • n=5 Participants
BMI (Body Mass Index)	31.26 kg/m^2 STANDARD_DEVIATION 4.26 • n=5 Participants	31.38 kg/m^2 STANDARD_DEVIATION 4.92 • n=7 Participants	31.32 kg/m^2 STANDARD_DEVIATION 4.60 • n=5 Participants
Stratification Metformin alone	62 participants n=5 Participants	64 participants n=7 Participants	126 participants n=5 Participants
Stratification Metformin + other OAD	84 participants n=5 Participants	86 participants n=7 Participants	170 participants n=5 Participants
HbA1c (glycosylated haemoglobin A1c)	8.89 percentage (%) of total haemoglobin STANDARD_DEVIATION 1.16 • n=5 Participants	8.67 percentage (%) of total haemoglobin STANDARD_DEVIATION 0.97 • n=7 Participants	8.78 percentage (%) of total haemoglobin STANDARD_DEVIATION 1.07 • n=5 Participants
Diabetes history	11.82 years STANDARD_DEVIATION 5.99 • n=5 Participants	12.68 years STANDARD_DEVIATION 6.68 • n=7 Participants	12.25 years STANDARD_DEVIATION 6.35 • n=5 Participants

PRIMARY outcome

Timeframe: week 36

Population: Full analysis set (FAS) is all randomised subjects exposed to at least one dose of trial products.

Analysed for the full analysis set.

Outcome measures

Measure	Advanced n=140 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=147 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Glycosylated Haemoglobin A1c (HbA1c)	7.67 percentage (%) of total haemoglobin Standard Error 0.09	7.61 percentage (%) of total haemoglobin Standard Error 0.08

PRIMARY outcome

Timeframe: week 36

Population: Per Protocol analysis set: All exposed subjects who completed the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the efficacy results.

Measured for the Per Protocol analysis set.

Outcome measures

Measure	Advanced n=107 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=118 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Glycosylated Haemoglobin A1c (HbA1c)	7.55 percentage (%) of total haemoglobin Standard Error 0.09	7.52 percentage (%) of total haemoglobin Standard Error 0.08

SECONDARY outcome

Timeframe: Weeks 0-36

Population: Safety Analysis Set is all randomised subjects exposed to at least one dose of trial products.

Number of hypoglycaemic episodes from Week 0 to Week 36, defined as major, minor or symptoms only. Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L (56 mg/dL). Symptoms only if able to treat her/himself and no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L.

Outcome measures

Measure	Advanced n=146 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=150 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Hypoglycaemic Episodes Major	1 episodes	4 episodes
Hypoglycaemic Episodes Minor	531 episodes	567 episodes
Hypoglycaemic Episodes Symptoms Only	283 episodes	344 episodes

SECONDARY outcome

Timeframe: week 36

Population: Safety Analysis Set is all randomised subjects exposed to at least one dose of trial products.

Alanine aminotransferase was measured in serum at week 36. Serum samples were analysed at a central laboratory.

Outcome measures

Measure	Advanced n=133 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=138 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Biochemistry: Serum Alanine Aminotransferase	30.09 U/L Standard Deviation 18.54	27.04 U/L Standard Deviation 14.64

SECONDARY outcome

Timeframe: week 36

Population: Safety Analysis Set is all randomised subjects exposed to at least one dose of trial products.

Haemoglobin was measured in blood samples at week 36. Blood samples were analysed at a central laboratory.

Outcome measures

Measure	Advanced n=128 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=136 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Haematology: Haemoglobin Measured in Blood	8.57 mmol/L Standard Deviation 0.87	8.58 mmol/L Standard Deviation 0.95

SECONDARY outcome

Timeframe: week 36

Population: Safety Analysis Set is all randomised subjects exposed to at least one dose of trial products.

High-sensitivity C-reactive peptide was measured in serum at week 36. Serum samples were analysed at a central laboratory.

Outcome measures

Measure	Advanced n=132 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=136 Participants Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Cardiovascular Risk Marker: High-sensitivity C-reactive Peptide	3.76 mg/L Standard Deviation 3.46	4.67 mg/L Standard Deviation 6.86

Adverse Events

Advanced

Serious events: 4 serious events

Other events: 54 other events

Deaths: 0 deaths

Basic

Serious events: 8 serious events

Other events: 58 other events

Deaths: 0 deaths

Serious adverse events

Measure	Advanced n=146 participants at risk Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=150 participants at risk Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast Cancer	0.68% 1/146 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.00% 0/150 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon Cancer	0.00% 0/146 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung Neoplasm	0.00% 0/146 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic Carcinoma	0.00% 0/146 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Cardiac disorders Myocardial Infarction	0.68% 1/146 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Cardiac disorders Cardiac Failure	0.00% 0/146 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Infections and infestations Cellulitis	0.68% 1/146 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.00% 0/150 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Infections and infestations Diabetic Foot Infection	0.00% 0/146 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Infections and infestations Pneumonia	0.00% 0/146 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Gastrointestinal disorders Duodenal Ulcer Haemorrhage	0.68% 1/146 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.00% 0/150 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Hepatobiliary disorders Cholecystitis Chronic	0.00% 0/146 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Injury, poisoning and procedural complications Accidental Overdose	0.00% 0/146 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	0.67% 1/150 • Number of events 1 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.

Other adverse events

Measure	Advanced n=146 participants at risk Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.	Basic n=150 participants at risk Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
Infections and infestations Nasopharyngitis	14.4% 21/146 • Number of events 24 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	11.3% 17/150 • Number of events 22 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Infections and infestations Upper respiratory tract infection	5.5% 8/146 • Number of events 11 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	3.3% 5/150 • Number of events 7 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Musculoskeletal and connective tissue disorders Back Pain	4.1% 6/146 • Number of events 7 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	5.3% 8/150 • Number of events 8 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Nervous system disorders Headache	8.9% 13/146 • Number of events 19 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	6.7% 10/150 • Number of events 13 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Respiratory, thoracic and mediastinal disorders Cough	2.7% 4/146 • Number of events 5 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	5.3% 8/150 • Number of events 8 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.
Vascular disorders Hypertension	5.5% 8/146 • Number of events 8 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.	6.7% 10/150 • Number of events 10 • The adverse events were collected in a timeframe of 36 weeks. Safety analysis set is all randomised subjects exposed to at least one dose of trial products.

Additional Information

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Email: clinicaltrials@novonordisk.com

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• Principal investigator is a sponsor employee Novo Nordisk maintains the right to be informed of any investigator plans for publication and to review any scientific paper, presentation, communication or other information concerning the investigation described in this protocol. Any such communication must be submitted in writing to the Novo Nordisk trial manager prior to submission for comments. Comments will be given within four weeks from receipt of the planned communication.
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