Trial Outcomes & Findings for Investigating Efficacy and Safety of Biphasic Insulin Aspart 50 Twice Daily Versus Biphasic Human Insulin 50 Twice Daily Both in Combination With Metformin in Chinese Subjects With Type 2 Diabetes Mellitus (NCT NCT01892020)

NCT ID: NCT01892020

Last Updated: 2015-07-09

Results Overview

The 2-hour PPG increment is the difference between the plasma glucose (PG) value at 120 minutes after standard meal test and the fasting PG value.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 161 participants
• Primary outcome timeframe: After 4 weeks of treatment in each treatment sequence
• Results posted on: 2015-07-09

Participant Flow

This trial was conducted in 14 sites in one country (China).

There were no significant events following enrolment of subjects, and prior to randomization.

Participant milestones

Measure	Group A (BIAsp 50 - BHI 50) In this multi-center, randomized, open-labelled, 2-sequence, 2-period crossover trial, the eligible subjects were randomized to 2 groups to receive biphasic insulin aspart 50 (BIAsp 50) and biphasic human insulin 50 (BHI 50) in different sequences. Group A received BIAsp 50 twice daily (BID) during the first 4 weeks (period 1), then switched to BHI 50 BID for further 4 weeks (period 2). BIAsp 50 (NovoMix® 50) was administered subcutaneously (s.c.) using NovoPen 4 immediately before breakfast and dinner. And BHI 50 was administered s.c. using NovoPen 4 at least 30 minutes before breakfast and dinner. All subjects received metformin throughout this trial. Insulin dose was adjusted twice weekly based on self-measured plasma glucose (SMPG).	Group B (BHI 50 - BIAsp 50) In this multi-center, randomized, open-labelled, 2-sequence, 2-period crossover trial, the eligible subjects were randomized to 2 groups to receive biphasic insulin aspart 50 (BIAsp 50) and biphasic human insulin 50 (BHI 50) in different sequences. Group B received BHI 50 twice daily (BID) during the first 4 weeks (period 1), then switched to BIAsp 50 BID for further 4 weeks (period 2). BIAsp 50 (NovoMix® 50) was administered subcutaneously (s.c.) using NovoPen 4 immediately before breakfast and dinner. And BHI 50 was administered s.c. using NovoPen 4 at least 30 minutes before breakfast and dinner. All subjects received metformin throughout this trial. Insulin dose was adjusted twice weekly based on self-measured plasma glucose (SMPG).
Period 1 STARTED	81	80
Period 1 COMPLETED	78	74
Period 1 NOT COMPLETED	3	6
Period 2 STARTED	78	74
Period 2 COMPLETED	77	74
Period 2 NOT COMPLETED	1	0

Reasons for withdrawal

Measure	Group A (BIAsp 50 - BHI 50) In this multi-center, randomized, open-labelled, 2-sequence, 2-period crossover trial, the eligible subjects were randomized to 2 groups to receive biphasic insulin aspart 50 (BIAsp 50) and biphasic human insulin 50 (BHI 50) in different sequences. Group A received BIAsp 50 twice daily (BID) during the first 4 weeks (period 1), then switched to BHI 50 BID for further 4 weeks (period 2). BIAsp 50 (NovoMix® 50) was administered subcutaneously (s.c.) using NovoPen 4 immediately before breakfast and dinner. And BHI 50 was administered s.c. using NovoPen 4 at least 30 minutes before breakfast and dinner. All subjects received metformin throughout this trial. Insulin dose was adjusted twice weekly based on self-measured plasma glucose (SMPG).	Group B (BHI 50 - BIAsp 50) In this multi-center, randomized, open-labelled, 2-sequence, 2-period crossover trial, the eligible subjects were randomized to 2 groups to receive biphasic insulin aspart 50 (BIAsp 50) and biphasic human insulin 50 (BHI 50) in different sequences. Group B received BHI 50 twice daily (BID) during the first 4 weeks (period 1), then switched to BIAsp 50 BID for further 4 weeks (period 2). BIAsp 50 (NovoMix® 50) was administered subcutaneously (s.c.) using NovoPen 4 immediately before breakfast and dinner. And BHI 50 was administered s.c. using NovoPen 4 at least 30 minutes before breakfast and dinner. All subjects received metformin throughout this trial. Insulin dose was adjusted twice weekly based on self-measured plasma glucose (SMPG).
Period 1 Adverse Event	1	1
Period 1 Protocol Violation	2	4
Period 1 Unclassified	0	1
Period 2 Protocol Violation	1	0

Baseline Characteristics

Investigating Efficacy and Safety of Biphasic Insulin Aspart 50 Twice Daily Versus Biphasic Human Insulin 50 Twice Daily Both in Combination With Metformin in Chinese Subjects With Type 2 Diabetes Mellitus

Baseline characteristics by cohort

Measure	All Subjects n=161 Participants In this multi-center, randomized, open-labelled, 2-sequence, 2-period crossover trial, the eligible subjects were randomized to 2 groups to receive biphasic insulin aspart 50 (BIAsp 50) and biphasic human insulin 50 (BHI 50) in different sequences. Group A received BIAsp 50 twice daily (BID) during the first 4 weeks (period 1), then switched to BHI 50 BID for further 4 weeks (period 2). Group B received BHI 50 BID during the first 4 weeks (period 1), then switched to BIAsp 50 BID for further 4 weeks (period 2). BIAsp 50 (NovoMix® 50) was administered subcutaneously (s.c.) using NovoPen 4 immediately before breakfast and dinner. And BHI 50 was administered s.c. using NovoPen 4 at least 30 minutes before breakfast and dinner. All subjects received metformin throughout this trial. Insulin dose was adjusted twice weekly based on self-measured plasma glucose (SMPG).
Age, Continuous	59.1 years STANDARD_DEVIATION 8.5 • n=5 Participants
Sex: Female, Male Female	88 Participants n=5 Participants
Sex: Female, Male Male	73 Participants n=5 Participants

PRIMARY outcome

Timeframe: After 4 weeks of treatment in each treatment sequence

Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Three (3) subjects in BIAsp 50 group and 9 subjects in BHI 50 group did not contribute to the analysis due to lack of post-randomization measurements.

The 2-hour PPG increment is the difference between the plasma glucose (PG) value at 120 minutes after standard meal test and the fasting PG value.

Outcome measures

Measure	BIAsp 50 n=152 Participants This arm included the subjects received BIAsp 50.	BHI 50 n=149 Participants This arm included the subjects received BHI 50.
2-hour PPG (Postprandial Plasma Glucose) Increment Following a Standard Meal Test	5.30 mmol/L Standard Deviation 3.17	6.41 mmol/L Standard Deviation 2.83

SECONDARY outcome

Timeframe: After 4 weeks of treatment in each treatment sequence

Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Three (3) subjects in BIAsp 50 group and 8 subjects in BHI 50 group did not contribute to the analysis due to lack of post-randomization measurements.

The 1-h PPG increment is the difference between the plasma glucose (PG) value at 60 minutes after standard meal test and the fasting PG value.

Outcome measures

Measure	BIAsp 50 n=152 Participants This arm included the subjects received BIAsp 50.	BHI 50 n=150 Participants This arm included the subjects received BHI 50.
-1-hour PPG Increment Following a Standard Meal Test	4.42 mmol/L Standard Deviation 2.49	4.74 mmol/L Standard Deviation 2.24

SECONDARY outcome

Timeframe: After 4 weeks of treatment in each treatment sequence

Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Three (3) subjects in BIAsp 50 group and 9 subjects in BHI 50 group did not contribute to the analysis due to lack of post-randomization measurements.

AUC for plasma glucose was calculated by the trapezoidal method using 30-min sampling time points, and IAUC for PPG (0-2h) data was analyzed using a normal linear mixed model.

Outcome measures

Measure	BIAsp 50 n=152 Participants This arm included the subjects received BIAsp 50.	BHI 50 n=149 Participants This arm included the subjects received BHI 50.
-IAUC (Incremental Area Under the Curve) for PPG (0-2 Hours) Following a Standard Meal Test	465.39 min*mmol/L Standard Deviation 228	503.64 min*mmol/L Standard Deviation 215

SECONDARY outcome

Timeframe: After 4 weeks of treatment in each treatment sequence

Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Subjects were excluded from analysis due to lack of post-randomization measurements. See table.

PPG increments over each of the 3 main meals were derived from the 8-point SMPG profile as the difference between PG values available 120 minutes after meal and before meal.

Outcome measures

Measure	BIAsp 50 n=151 Participants This arm included the subjects received BIAsp 50.	BHI 50 n=149 Participants This arm included the subjects received BHI 50.
2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile Increment at breakfast, N=151, 149	2.52 mmol/L Standard Error 0.20	2.86 mmol/L Standard Error 0.20
2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile Increment at Lunch, N=150, 148	3.58 mmol/L Standard Error 0.26	2.93 mmol/L Standard Error 0.26
2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile Increment at dinner, N=151, 149	1.08 mmol/L Standard Error 0.26	0.99 mmol/L Standard Error 0.26

SECONDARY outcome

Timeframe: After 4 weeks of treatment in each treatment sequence

Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Four (4) subjects in BIAsp 50 group and 9 subjects in BHI 50 group did not contribute to the analysis due to lack of post-randomization measurements.

Mean post prandial PG increment over all meals was derived as the mean of all available meal increments.

Outcome measures

Measure	BIAsp 50 n=151 Participants This arm included the subjects received BIAsp 50.	BHI 50 n=149 Participants This arm included the subjects received BHI 50.
The Mean 2-hour PPG Increments of the 3 Main Meals in 8-point SMPG Profile	2.39 mmol/L Standard Error 0.15	2.25 mmol/L Standard Error 0.15

SECONDARY outcome

Timeframe: During 4 weeks of treatment in each treatment sequence

Population: Safety analysis set included all subjects receiving at least one dose of investigational products.

Treatment Emergent Hypoglycemic Episode refers to those the onset of the episode is on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment. Results are presented by American Diabetes Association classification of hypoglycemia.

Outcome measures

Measure	BIAsp 50 n=155 Participants This arm included the subjects received BIAsp 50.	BHI 50 n=158 Participants This arm included the subjects received BHI 50.
Incidence of Hypoglycemic Episodes All events	12.10 events per patient per year	14.38 events per patient per year
Incidence of Hypoglycemic Episodes Severe	0 events per patient per year	0.08 events per patient per year
Incidence of Hypoglycemic Episodes Documented Symptomatic	5.97 events per patient per year	8.33 events per patient per year
Incidence of Hypoglycemic Episodes Asymptomatic	1.29 events per patient per year	2.53 events per patient per year
Incidence of Hypoglycemic Episodes Probable Symptomatic	2.58 events per patient per year	1.72 events per patient per year
Incidence of Hypoglycemic Episodes Relative	2.10 events per patient per year	1.72 events per patient per year
Incidence of Hypoglycemic Episodes Unclassifiable	0.16 events per patient per year	0 events per patient per year

SECONDARY outcome

Timeframe: During 4 weeks of treatment in each treatment sequence

Population: Safety analysis set included all subjects receiving at least one dose of investigational products.

Treatment emergent AE (TEAE) is defined as an event that has onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment.

Outcome measures

Measure	BIAsp 50 n=155 Participants This arm included the subjects received BIAsp 50.	BHI 50 n=158 Participants This arm included the subjects received BHI 50.
Incidence of AEs (Adverse Event)	322.7 Events/100 years of patient exposure	245.1 Events/100 years of patient exposure

Adverse Events

BIAsp 50

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

BHI 50

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	BIAsp 50 n=155 participants at risk This arm included the subjects received BIAsp 50.	BHI 50 n=158 participants at risk This arm included the subjects received BHI 50.
General disorders Small intestinal haemorrhage	0.00% 0/155 • An event with onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment was defined as treatment emergent AE. All events meeting this definition were collected and reported. Safety analysis set included all subjects receiving at least one dose of investigational products.	0.63% 1/158 • Number of events 1 • An event with onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment was defined as treatment emergent AE. All events meeting this definition were collected and reported. Safety analysis set included all subjects receiving at least one dose of investigational products.
Nervous system disorders Cerebral infarction	0.65% 1/155 • Number of events 1 • An event with onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment was defined as treatment emergent AE. All events meeting this definition were collected and reported. Safety analysis set included all subjects receiving at least one dose of investigational products.	0.00% 0/158 • An event with onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment was defined as treatment emergent AE. All events meeting this definition were collected and reported. Safety analysis set included all subjects receiving at least one dose of investigational products.

Other adverse events

Measure	BIAsp 50 n=155 participants at risk This arm included the subjects received BIAsp 50.	BHI 50 n=158 participants at risk This arm included the subjects received BHI 50.
Metabolism and nutrition disorders Hyperlipidaemia	5.2% 8/155 • Number of events 8 • An event with onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment was defined as treatment emergent AE. All events meeting this definition were collected and reported. Safety analysis set included all subjects receiving at least one dose of investigational products.	1.3% 2/158 • Number of events 2 • An event with onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment was defined as treatment emergent AE. All events meeting this definition were collected and reported. Safety analysis set included all subjects receiving at least one dose of investigational products.

Additional Information

Public Access to Clinical Trials

Novo Nordisk A/S

Email: clinicaltrials@novonordisk.com

Results disclosure agreements

• Principal investigator is a sponsor employee Authorship of publications should be in accordance with the Uniform Requirements of the International Committee of Medical Journal Editors. The Investigators offered authorship will be asked to comment and approve the publication. No permission to publish will be granted to any clinical research organization involved in the trial described in trial protocol.
• Publication restrictions are in place

Restriction type: OTHER