Trial Outcomes & Findings for Comparison of Two NN5401 Formulations Versus Insulin Glargine, All in Combination With Metformin in Subjects With Type 2 Diabetes (NCT NCT00614055)

Results Overview

Change from baseline in HbA1c after 16 weeks of treatment

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

178 participants

Primary outcome timeframe

Week 0, Week 16

Results posted on

2017-03-20

Participant Flow

The trial was conducted at 22 sites in 5 countries: France (4 sites), Germany (5 sites), Norway (5 sites), Romania (3 sites) and Spain (5 sites).

During a run-in period of 2 weeks, metformin was up-titrated to 1500/ 2000 mg/day, which was maintained for 1 week. Subjects who tolerated the metformin dose for a week and had a median of 3 self measured glucose values before breakfast, on 3 consecutive days before randomisation, of ≥ 7.5 mmol/l, were randomised to 1 of the 3 treatment groups

Participant milestones

Participant milestones
Measure	SIAC 30 (B) Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 45 (B) Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin Glargine Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Overall Study STARTED	59	59	60
Overall Study Exposed	59	59	60
Overall Study COMPLETED	55	53	55
Overall Study NOT COMPLETED	4	6	5

Reasons for withdrawal

Reasons for withdrawal
Measure	SIAC 30 (B) Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 45 (B) Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin Glargine Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Overall Study Adverse Event	1	0	0
Overall Study Protocol Violation	2	2	1
Overall Study Lack of Efficacy	0	0	2
Overall Study Unclassified	1	4	2

Baseline Characteristics

Comparison of Two NN5401 Formulations Versus Insulin Glargine, All in Combination With Metformin in Subjects With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SIAC 30 (B) n=59 Participants Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 45 (B) n=59 Participants Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin Glargine n=60 Participants Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Total n=178 Participants Total of all reporting groups
Age, Continuous	58.7 years STANDARD_DEVIATION 8.8 • n=5 Participants	60.2 years STANDARD_DEVIATION 8.4 • n=7 Participants	58.4 years STANDARD_DEVIATION 8.4 • n=5 Participants	59.1 years STANDARD_DEVIATION 8.5 • n=4 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	25 Participants n=7 Participants	16 Participants n=5 Participants	63 Participants n=4 Participants
Sex: Female, Male Male	37 Participants n=5 Participants	34 Participants n=7 Participants	44 Participants n=5 Participants	115 Participants n=4 Participants
Glycosylated haemoglobin (HbA1c)	8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.2 • n=5 Participants	8.6 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.5 • n=7 Participants	8.4 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.3 • n=5 Participants	8.5 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.3 • n=4 Participants
Fasting plasma glucose (FPG)	11.1 mmol/L STANDARD_DEVIATION 3.3 • n=5 Participants	11.5 mmol/L STANDARD_DEVIATION 3.2 • n=7 Participants	12.1 mmol/L STANDARD_DEVIATION 3.5 • n=5 Participants	11.6 mmol/L STANDARD_DEVIATION 3.3 • n=4 Participants

PRIMARY outcome

Timeframe: Week 0, Week 16

Population: Full analysis set (FAS) included all randomised subjects and missing data was imputed using last observation carried forward (LOCF).

Change from baseline in HbA1c after 16 weeks of treatment

Outcome measures

Outcome measures
Measure	Insulin Glargine n=60 Participants Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 30 (B) n=59 Participants Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 45 (B) n=59 Participants Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Change in Glycosylated Haemoglobin (HbA1c)	-1.29 percentage of glycosylated haemoglobin Standard Deviation 1.10	-1.31 percentage of glycosylated haemoglobin Standard Deviation 1.01	-1.46 percentage of glycosylated haemoglobin Standard Deviation 1.39

SECONDARY outcome

Timeframe: Week 0, Week 16

Population: The FAS included all randomised subjects and missing data was imputed using LOCF.

Change from baseline in FPG after 16 weeks of treatment

Outcome measures

Outcome measures
Measure	Insulin Glargine n=60 Participants Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 30 (B) n=59 Participants Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 45 (B) n=59 Participants Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Change in Fasting Plasma Glucose (FPG)	-5.07 mmol/L Standard Deviation 3.85	-4.30 mmol/L Standard Deviation 3.45	-4.10 mmol/L Standard Deviation 3.09

SECONDARY outcome

Timeframe: Week 16

Population: The FAS included all randomised subjects and missing data was imputed using LOCF.

Mean of SMPG after 16 weeks of treatment. Plasma glucose measured: before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner, bedtime, at 4 am and before breakfast.

Outcome measures

Outcome measures
Measure	Insulin Glargine n=60 Participants Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 30 (B) n=59 Participants Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 45 (B) n=59 Participants Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Mean of 9-point Self Measured Plasma Glucose Profile (SMPG)	8.42 mmol/L Standard Error 0.78	8.34 mmol/L Standard Error 0.75	8.31 mmol/L Standard Error 0.78

SECONDARY outcome

Timeframe: Week 0 to Week 16 + 5 days follow up

Population: Safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or its comparator.

Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect.

Outcome measures

Outcome measures
Measure	Insulin Glargine n=60 Participants Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 30 (B) n=59 Participants Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 45 (B) n=59 Participants Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Rate of Treatment Emergent Adverse Events (AEs) Adverse events (AEs)	295 Events/100 years of patient exposure	441 Events/100 years of patient exposure	310 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Serious AEs	0 Events/100 years of patient exposure	11 Events/100 years of patient exposure	6 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Severe AEs	0 Events/100 years of patient exposure	6 Events/100 years of patient exposure	0 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Moderate AEs	61 Events/100 years of patient exposure	138 Events/100 years of patient exposure	123 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Mild AEs	234 Events/100 years of patient exposure	298 Events/100 years of patient exposure	187 Events/100 years of patient exposure
Rate of Treatment Emergent Adverse Events (AEs) Fatal AEs	0 Events/100 years of patient exposure	0 Events/100 years of patient exposure	0 Events/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0 to Week 16 + 5 days follow up

Population: The FAS included all randomised subjects.

Rate of Major and Minor hypoglycaemic episodes per 100 patient years of exposure (PYE). Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L.

Outcome measures

Outcome measures
Measure	Insulin Glargine n=60 Participants Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 30 (B) n=59 Participants Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	SIAC 45 (B) n=59 Participants Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Rate of Major and Minor Hypoglycaemic Episodes Major	0 Episodes/100 years of patient exposure	0 Episodes/100 years of patient exposure	0 Episodes/100 years of patient exposure
Rate of Major and Minor Hypoglycaemic Episodes Minor	67 Episodes/100 years of patient exposure	115 Episodes/100 years of patient exposure	240 Episodes/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0 to Week 16 + 5 days follow up

Population: The FAS included all randomised subjects.

Rate of nocturnal Major and Minor hypoglycaemic episodes per 100 patient years of exposure (PYE). Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L. Episodes were defined as nocturnal if the time of onset was between 23:00 (included) and 06:00 (excluded).