Trial Outcomes & Findings for Efficacy and Safety of FIAsp Compared to Insulin Aspart in Combination With Insulin Glargine and Metformin in Adults With Type 2 Diabetes (NCT NCT01819129)

NCT ID: NCT01819129

Last Updated: 2019-01-30

Results Overview

The primary endpoint was change from baseline in HbA1c after 26 weeks of randomized treatment. For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

881 participants

Primary outcome timeframe

Week 0, Week 26

Results posted on

2019-01-30

Participant Flow

Out of 150 sites, which were selected for recruitment, 128 sites in 9 countries enrolled subjects in the run-in period, of which 123 sites later assigned subjects to randomized treatment: Canada:9 sites; Croatia:6 sites; India:6 sites; Israel:6 sites; Russia:12 sites; Serbia:9 sites; Slovakia:5 sites; United Kingdom:7 sites; United States:63 sites.

The trial included an 8-week run-in period and a 26-week treatment period. During the run-in period, the subjects received insulin glargine along with metformin. In total, 881 subjects entered the run-in period, of these 192 subjects were run-in failures. Hence, 689 subjects entered the 26-week treatment period.

Participant milestones

Participant milestones
Measure	Faster Aspart At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily subcutaneous (sc) injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	NovoRapid At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Overall Study STARTED	345	344
Overall Study Exposed	341	341
Overall Study COMPLETED	301	305
Overall Study NOT COMPLETED	44	39

Reasons for withdrawal

Reasons for withdrawal
Measure	Faster Aspart At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily subcutaneous (sc) injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	NovoRapid At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Overall Study Other, Subject wanted HbA1c to be > 7%	1	0
Overall Study Other, weight gain, hypoglycaemic events	1	0
Overall Study Other, Subject moved out of the country	0	1
Overall Study Withdrawal by Subject	15	15
Overall Study Lost to Follow-up	5	2
Overall Study Lack of Efficacy	0	1
Overall Study Adverse Event	1	4
Overall Study Death	1	1
Overall Study Withdrawal Criteria	20	15

Baseline Characteristics

Efficacy and Safety of FIAsp Compared to Insulin Aspart in Combination With Insulin Glargine and Metformin in Adults With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Faster Aspart n=345 Participants At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	NovoRapid n=344 Participants At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	Total n=689 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	241 Participants n=5 Participants	248 Participants n=7 Participants	489 Participants n=5 Participants
Age, Categorical >=65 years	104 Participants n=5 Participants	96 Participants n=7 Participants	200 Participants n=5 Participants
Age, Continuous	59.6 Years STANDARD_DEVIATION 9.3 • n=5 Participants	59.4 Years STANDARD_DEVIATION 9.6 • n=7 Participants	59.5 Years STANDARD_DEVIATION 9.4 • n=5 Participants
Sex: Female, Male Female	182 Participants n=5 Participants	171 Participants n=7 Participants	353 Participants n=5 Participants
Sex: Female, Male Male	163 Participants n=5 Participants	173 Participants n=7 Participants	336 Participants n=5 Participants
Glycosylated haemoglobin A1c (HbA1c)	7.96 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.68 • n=5 Participants	7.89 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.71 • n=7 Participants	7.92 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.70 • n=5 Participants
Body Weight	89.0 Kg STANDARD_DEVIATION 16.9 • n=5 Participants	88.3 Kg STANDARD_DEVIATION 16.7 • n=7 Participants	88.7 Kg STANDARD_DEVIATION 16.8 • n=5 Participants

PRIMARY outcome

Timeframe: Week 0, Week 26

Population: The analysis of this efficacy endpoint was based on the full analysis set (FAS). FAS included all randomized subjects. The statistical evaluation of the FAS was to follow the intention-to-treat (ITT) principle and subjects contributed to the evaluation 'as randomized'.

Outcome measures

Outcome measures
Measure	Faster Aspart n=345 Participants At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	NovoRapid n=344 Participants At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Change From Baseline in HbA1c Baseline (week 0)	7.96 Percentage of glycosylated haemoglobin Standard Deviation 0.68	7.89 Percentage of glycosylated haemoglobin Standard Deviation 0.71
Change From Baseline in HbA1c Week 26	6.63 Percentage of glycosylated haemoglobin Standard Deviation 0.88	6.59 Percentage of glycosylated haemoglobin Standard Deviation 0.84

SECONDARY outcome

Timeframe: Week 0, week 26

Population: This endpoint was summarized using the Full Analysis Set (FAS). FAS included all randomized subjects.

For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.

Outcome measures

Outcome measures
Measure	Faster Aspart n=345 Participants At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	NovoRapid n=344 Participants At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Change From Baseline in 2-hour PPG Increment (Meal Test) Baseline (week 0)	7.57 mmol/L Standard Deviation 3.19	7.34 mmol/L Standard Deviation 3.12
Change From Baseline in 2-hour PPG Increment (Meal Test) Week 26	4.55 mmol/L Standard Deviation 3.13	4.9 mmol/L Standard Deviation 3.36

SECONDARY outcome

Timeframe: From Week 0 to Week 26.

Population: This endpoint was summarized using the safety analysis set. Safety analysis set included all subjects receiving at least one dose of the test product or comparator. Subjects in the safety analysis set contributed to the evaluation 'as treated'.

A hypoglycaemic episode was defined as treatment-emergent if the onset of the episode was on or after the first day of exposure to randomized treatment and no later than 1 day after the last day of randomized treatment. A severe or blood glucose (BG) confirmed hypoglycaemic episode was an episode that was severe according to the American Diabetes Association (ADA) classification (an episode that required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia.

Outcome measures

Outcome measures
Measure	Faster Aspart n=341 Participants At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	NovoRapid n=341 Participants At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Number of Treatment Emergent Confirmed Hypoglycaemic Episodes	2857 Number of episodes	2692 Number of episodes

SECONDARY outcome

Timeframe: Week 0, week 26

Population: This endpoint was summarized using the FAS. FAS included all randomized subjects.

For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.

Outcome measures

Outcome measures
Measure	Faster Aspart n=345 Participants At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	NovoRapid n=344 Participants At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Change From Baseline in Body Weight Baseline (week 0)	89.0 Kg Standard Deviation 16.9	88.3 Kg Standard Deviation 16.7
Change From Baseline in Body Weight Week 26	91.6 Kg Standard Deviation 18.2	90.8 Kg Standard Deviation 17.7

Adverse Events

Faster Aspart

Serious events: 15 serious events

Other events: 49 other events

Deaths: 0 deaths

NovoRapid

Serious events: 24 serious events

Other events: 53 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Faster Aspart n=341 participants at risk At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	NovoRapid n=341 participants at risk At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Infections and infestations Nasopharyngitis	5.0% 17/341 • Number of events 20 • All treatment-emergent adverse events (AEs) were collected from the date on or after the first day of exposure to randomized treatment until no later than 7 days after the last day of randomised treatment Safety analysis set was used for the assessment of safety including AEs. The safety analysis set included all subjects who received at least one dose of test product (faster aspart) or comparator(NovoRapid).	7.0% 24/341 • Number of events 27 • All treatment-emergent adverse events (AEs) were collected from the date on or after the first day of exposure to randomized treatment until no later than 7 days after the last day of randomised treatment Safety analysis set was used for the assessment of safety including AEs. The safety analysis set included all subjects who received at least one dose of test product (faster aspart) or comparator(NovoRapid).
Infections and infestations Upper respiratory tract infection	4.7% 16/341 • Number of events 19 • All treatment-emergent adverse events (AEs) were collected from the date on or after the first day of exposure to randomized treatment until no later than 7 days after the last day of randomised treatment Safety analysis set was used for the assessment of safety including AEs. The safety analysis set included all subjects who received at least one dose of test product (faster aspart) or comparator(NovoRapid).	6.5% 22/341 • Number of events 27 • All treatment-emergent adverse events (AEs) were collected from the date on or after the first day of exposure to randomized treatment until no later than 7 days after the last day of randomised treatment Safety analysis set was used for the assessment of safety including AEs. The safety analysis set included all subjects who received at least one dose of test product (faster aspart) or comparator(NovoRapid).
Infections and infestations Urinary tract infection	5.9% 20/341 • Number of events 27 • All treatment-emergent adverse events (AEs) were collected from the date on or after the first day of exposure to randomized treatment until no later than 7 days after the last day of randomised treatment Safety analysis set was used for the assessment of safety including AEs. The safety analysis set included all subjects who received at least one dose of test product (faster aspart) or comparator(NovoRapid).	3.8% 13/341 • Number of events 16 • All treatment-emergent adverse events (AEs) were collected from the date on or after the first day of exposure to randomized treatment until no later than 7 days after the last day of randomised treatment Safety analysis set was used for the assessment of safety including AEs. The safety analysis set included all subjects who received at least one dose of test product (faster aspart) or comparator(NovoRapid).

Additional Information

Clinical Reporting Anchor and Disclosure (1452)

Novo Nordisk A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee At the end of the trial, one or more public disclosures may be prepared collaboratively by the Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.
Publication restrictions are in place

Restriction type: OTHER