Trial Outcomes & Findings for Comparison of Biphasic Insulin Aspart 30 Versus Insulin Glargine Both in Combination With Metformin and Glimepiride in Subjects With Type 2 Diabetes (NCT NCT00469092)

NCT ID: NCT00469092

Last Updated: 2017-02-23

Results Overview

Glycosylated Haemoglobin A1c measured in blood samples after 26 weeks of treatment.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

480 participants

Primary outcome timeframe

After 26 weeks of treatment

Results posted on

2017-02-23

Participant Flow

Subjects were enrolled 64 sites in 15 countries in Africa, Europe, Asia, North America and South America.

A screening period of 1-2 weeks was followed by a run-in period of 4 weeks during which metformin was titrated to maximum 2550 mg and glimepiride to 4 mg, at the discretion of the investigator. Subjects who were already taking 4, 6 or 8 mg glimepiride continued on this dose. Doses were kept constant during the last week prior to randomisation.

Participant milestones

Participant milestones
Measure	BIAsp 30 Biphasic insulin aspart 30 + metformin + glimepiride	Glargine Insulin glargine + metformin + glimepiride
Overall Study STARTED	239	241
Overall Study Exposed to Study Drug	231	238
Overall Study COMPLETED	213	220
Overall Study NOT COMPLETED	26	21

Reasons for withdrawal

Reasons for withdrawal
Measure	BIAsp 30 Biphasic insulin aspart 30 + metformin + glimepiride	Glargine Insulin glargine + metformin + glimepiride
Overall Study Adverse Event	5	4
Overall Study Lack of Efficacy	1	0
Overall Study Lost to Follow-up	1	2
Overall Study Protocol Violation	3	3
Overall Study Withdrawal by Subject	4	4
Overall Study Withdrawal Criteria	3	4
Overall Study Incorrectly Randomised	4	3
Overall Study Contraindication metformin/glimepiride	1	0
Overall Study Use of lipid lowering drug	1	0
Overall Study Hypoglycaemic Episodes	1	1
Overall Study Abnormal lab value	1	0
Overall Study Use of Corticosteroid	1	0

Baseline Characteristics

Comparison of Biphasic Insulin Aspart 30 Versus Insulin Glargine Both in Combination With Metformin and Glimepiride in Subjects With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BIAsp 30 n=231 Participants Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=238 Participants Insulin glargine + metformin + glimepiride	Total n=469 Participants Total of all reporting groups
Age, Continuous	55.9 years STANDARD_DEVIATION 9.7 • n=99 Participants	56.1 years STANDARD_DEVIATION 10.0 • n=107 Participants	56.0 years STANDARD_DEVIATION 9.9 • n=206 Participants
Gender Female	123 Participants n=99 Participants	140 Participants n=107 Participants	263 Participants n=206 Participants
Gender Male	108 Participants n=99 Participants	98 Participants n=107 Participants	206 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	35 Participants n=99 Participants	40 Participants n=107 Participants	75 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	192 Participants n=99 Participants	196 Participants n=107 Participants	388 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=99 Participants	2 Participants n=107 Participants	6 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	13 Participants n=99 Participants	11 Participants n=107 Participants	24 Participants n=206 Participants
Race (NIH/OMB) Asian	76 Participants n=99 Participants	79 Participants n=107 Participants	155 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	10 Participants n=99 Participants	7 Participants n=107 Participants	17 Participants n=206 Participants
Race (NIH/OMB) White	125 Participants n=99 Participants	133 Participants n=107 Participants	258 Participants n=206 Participants
Race (NIH/OMB) More than one race	3 Participants n=99 Participants	6 Participants n=107 Participants	9 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=99 Participants	2 Participants n=107 Participants	6 Participants n=206 Participants
BMI	29.0 kg/m^2 STANDARD_DEVIATION 4.6 • n=99 Participants	29.1 kg/m^2 STANDARD_DEVIATION 4.6 • n=107 Participants	29.1 kg/m^2 STANDARD_DEVIATION 4.6 • n=206 Participants
Diabetes duration	9.1 years STANDARD_DEVIATION 5.8 • n=99 Participants	9.5 years STANDARD_DEVIATION 6.1 • n=107 Participants	9.3 years STANDARD_DEVIATION 6.0 • n=206 Participants
HbA1c	8.9 percentage of total haemoglobin STANDARD_DEVIATION 1.0 • n=99 Participants	9.0 percentage of total haemoglobin STANDARD_DEVIATION 1.1 • n=107 Participants	9.0 percentage of total haemoglobin STANDARD_DEVIATION 1.1 • n=206 Participants
Weight	77.5 kg STANDARD_DEVIATION 14.6 • n=99 Participants	77.3 kg STANDARD_DEVIATION 15.4 • n=107 Participants	77.4 kg STANDARD_DEVIATION 15.0 • n=206 Participants

PRIMARY outcome

Timeframe: After 26 weeks of treatment

Population: Intention to Treat (Last Observation Carried Forward) population. All randomised subjects exposed to trial drug, and who had at least a baseline HbA1c measurement and at least one post randomisation HbA1c measurement.

Glycosylated Haemoglobin A1c measured in blood samples after 26 weeks of treatment.

Outcome measures

Outcome measures
Measure	BIAsp 30 n=225 Participants Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=232 Participants Insulin glargine + metformin + glimepiride
Glycosylated Haemoglobin A1c (HbA1c)	7.08 percentage of total haemoglobin Standard Deviation 0.07	7.23 percentage of total haemoglobin Standard Deviation 0.07

SECONDARY outcome

Timeframe: After 26 weeks of treatment

Population: Intention to Treat, Last Observation Carried Forward population. All randomised subjects exposed to trial drug, and who had at least a baseline HbA1c measurement and at least one post randomisation HbA1c measurement.

Glycaemic control measured by 9-point self-measured plasma glucose (SMPG) profiles. The 9 time points for self-measurement during the day were: Before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, before bedtime, at 2-4 AM, and before breakfast the following day. Hypoglycaemia episodes were defined as major or minor. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL.

Outcome measures

Outcome measures
Measure	BIAsp 30 n=225 Participants Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=232 Participants Insulin glargine + metformin + glimepiride
9-point Self-measured Plasma Glucose Profiles Before breakfast	6.73 mmol/L Standard Error 0.12	6.56 mmol/L Standard Error 0.12
9-point Self-measured Plasma Glucose Profiles 2 hours after breakfast	9.40 mmol/L Standard Error 0.20	9.07 mmol/L Standard Error 0.20
9-point Self-measured Plasma Glucose Profiles Before lunch	7.24 mmol/L Standard Error 0.18	7.28 mmol/L Standard Error 0.18
9-point Self-measured Plasma Glucose Profiles 2 hours after lunch	8.90 mmol/L Standard Error 0.20	8.98 mmol/L Standard Error 0.20
9-point Self-measured Plasma Glucose Profiles Before dinner	7.90 mmol/L Standard Error 0.18	7.80 mmol/L Standard Error 0.18
9-point Self-measured Plasma Glucose Profiles 2 hours after dinner	8.66 mmol/L Standard Error 0.19	9.18 mmol/L Standard Error 0.19
9-point Self-measured Plasma Glucose Profiles Before bedtime	7.77 mmol/L Standard Error 0.18	8.54 mmol/L Standard Error 0.18
9-point Self-measured Plasma Glucose Profiles 02:00-04:00 AM	6.56 mmol/L Standard Error 0.14	6.69 mmol/L Standard Error 0.14
9-point Self-measured Plasma Glucose Profiles Before breakfast following day	6.65 mmol/L Standard Error 0.12	6.40 mmol/L Standard Error 0.12

SECONDARY outcome

Timeframe: After 26 weeks of treatment

The number of subjects achieving the treatment target for glycosylated haemoglobin A1c after 26 weeks treatment. The treatment targets were: HbA1c \<= 6.5% of haemoglobin and HbA1c \< 7% of haemoglobin.

Outcome measures

Outcome measures
Measure	BIAsp 30 n=225 Participants Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=232 Participants Insulin glargine + metformin + glimepiride
Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) HbA1c <= 6.5% of haemoglobin	54 participants	60 participants
Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) HbA1c < 7.0% of haemoglobin	101 participants	106 participants
Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) Reduction > 1% point from baseline	134 participants	132 participants
Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) HbA1c < 7% no nocturnal hypoglycemia	82 participants	92 participants
Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) HbA1c < 7%, no daytime hypoglycemia	52 participants	50 participants
Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) HbA1c < 7%, no hypoglycemia	45 participants	45 participants

SECONDARY outcome

Timeframe: After 26 weeks of treatment

Subjects assessed the burden, efficacy, symptoms and overall score in the treatment satisfaction questionnaire, Diab MedSat (Diabetes Medication Satisfaction questionnaire). The scores were transformed to a 0-100 scale with higher scores indicating greater satisfaction. The score of the subscales was computed as the mean of the items in each subscale.

Outcome measures

Outcome measures
Measure	BIAsp 30 n=225 Participants Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=232 Participants Insulin glargine + metformin + glimepiride
Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) Burden Score	83.10 scores on a scale Standard Error 1.13	83.06 scores on a scale Standard Error 1.16
Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) Efficacy Score	73.25 scores on a scale Standard Error 1.57	73.47 scores on a scale Standard Error 1.57
Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) Symptoms Score	72.42 scores on a scale Standard Error 1.29	72.81 scores on a scale Standard Error 1.29
Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) Overall Score	76.53 scores on a scale Standard Error 1.04	76.64 scores on a scale Standard Error 1.05

SECONDARY outcome

Timeframe: Weeks 0-26

Total number of hypoglycaemic episodes experienced in each treatment arm. Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL. Symptoms only if subject was able to treat her/himself and with either no plasma glucose or blood glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L or 56 mg/dL.

Outcome measures

Outcome measures
Measure	BIAsp 30 n=231 Participants Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=238 Participants Insulin glargine + metformin + glimepiride
Number of Hypoglycaemic Episodes Minor	443 events	318 events
Number of Hypoglycaemic Episodes Symptom only	265 events	224 events
Number of Hypoglycaemic Episodes Major	3 events	3 events
Number of Hypoglycaemic Episodes Unclassified	1 events	0 events

SECONDARY outcome

Timeframe: Weeks 0-26

Population: The safety analysis population consists of all subjects exposed to trial products.

Number of subjects reporting treatment emergent adverse events during the trial (from week 0 to week 26). Adverse events were reported as treatment emergent if they occurred from the date of first insulin trial product administration up to and including the date of last insulin trial product administration.

Outcome measures

Outcome measures
Measure	BIAsp 30 n=231 Participants Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=238 Participants Insulin glargine + metformin + glimepiride
Number of Subjects Reporting Treatment Emergent Adverse Events	117 participants	115 participants

Adverse Events

BIAsp 30

Serious events: 13 serious events

Other events: 56 other events

Deaths: 0 deaths

Glargine

Serious events: 10 serious events

Other events: 63 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	BIAsp 30 n=231 participants at risk Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=238 participants at risk Insulin glargine + metformin + glimepiride
Gastrointestinal disorders Diarrhoea	3.5% 8/231 • Number of events 10 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	5.5% 13/238 • Number of events 14 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Nasopharyngitis	8.7% 20/231 • Number of events 22 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	8.4% 20/238 • Number of events 23 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Upper Respiratory Tract Infection	4.3% 10/231 • Number of events 12 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	5.9% 14/238 • Number of events 20 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Nervous system disorders Headache	7.8% 18/231 • Number of events 29 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	6.7% 16/238 • Number of events 40 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.

Additional Information

Public Access to Clinical Trials

Novo Nordisk A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Novo Nordisk maintains the right to be informed of any plans for publications 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	BIAsp 30 n=231 participants at risk Biphasic insulin aspart 30 + metformin + glimepiride	Glargine n=238 participants at risk Insulin glargine + metformin + glimepiride
Hepatobiliary disorders Biliary Colic	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Gastroenteritis	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Gastroenteritis Escherichia Coli	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Otitis Media Chronic	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Perianal Abscess	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Pneumonia	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Pneumonia Primary Atypical	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Infections and infestations Postoperative Wound Infection	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Injury, poisoning and procedural complications Femoral Neck Fracture	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Injury, poisoning and procedural complications Vascular Graft Occlusion	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Metabolism and nutrition disorders Diabetic Foot	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.84% 2/238 • Number of events 2 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Metabolism and nutrition disorders Hypoglycaemic Unconsciousness	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Musculoskeletal and connective tissue disorders Dupuytren's Contracture	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Nervous system disorders Cerebral Infarction	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Nervous system disorders Cerebrovascular Accident	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.84% 2/238 • Number of events 2 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Nervous system disorders Guillain-Barre Syndrome	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Nervous system disorders Hypoglycaemic Coma	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Respiratory, thoracic and mediastinal disorders Acute Pulmonary Oedema	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Surgical and medical procedures Wart Excision	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Vascular disorders Arterial Thrombosis Limb	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 2 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Vascular disorders Hypertensive Crisis	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Cardiac disorders Acute Myocardial Infarction	0.00% 0/231 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.42% 1/238 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.
Cardiac disorders Angina Unstable	0.43% 1/231 • Number of events 1 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.	0.00% 0/238 • The adverse event were collected in a time span of 26 weeks. The safety analysis population consists of all subjects exposed to trial products.