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Efficacy and Safety of FIAsp in a Basal-bolus Regimen Versus Basal Insulin Therapy, Both in Combination With Metformin in Adult Subjects With Type 2 Diabetes (onset® 3)

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ClinicalTrials.gov Identifier: NCT01850615
Recruitment Status : Completed
First Posted : May 9, 2013
Results First Posted : January 17, 2018
Last Update Posted : January 29, 2019
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 2
Interventions Drug: Faster-acting insulin aspart
Drug: basal insulin
Enrollment 323
Recruitment Details The trial was conducted at 51 sites in 6 countries as follows: Argentina: 4 sites; India: 8 sites; Mexico: 3 sites; Romania: 5 sites; Slovenia: 4 sites; United States: 27 sites.
Pre-assignment Details A total of 555 subjects were screened, of which 232 subjects were screening failures and 323 subjects were enrolled and entered the run-in (pre-assignment) period. Of those, 87 subjects were run-in failures. Hence, 236 subjects were randomized to the 18 weeks of treatment period.
Arm/Group Title Faster Aspart + Basal Basal
Hide Arm/Group Description During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different plasma glucose (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given once daily (OD), in the evening, at approximately the same time each day. During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Period Title: Overall Study
Started 116 120
Exposed 115 120
Completed 107 115
Not Completed 9 5
Reason Not Completed
Protocol Violation             4             1
Adverse Event             2             1
Withdrawal by Subject             3             1
Lost to Follow-up             0             1
Unclassified             0             1
Arm/Group Title Faster Aspart + Basal Basal Total
Hide Arm/Group Description During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day. During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day. Total of all reporting groups
Overall Number of Baseline Participants 116 120 236
Hide Baseline Analysis Population Description
Full analysis set (FAS) included all randomised subjects
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 116 participants 120 participants 236 participants
57.5  (9.9) 57.4  (8.5) 57.4  (9.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 116 participants 120 participants 236 participants
Female
61
  52.6%
61
  50.8%
122
  51.7%
Male
55
  47.4%
59
  49.2%
114
  48.3%
Glycosylated haemoglobin (HbA1c)  
Mean (Standard Deviation)
Unit of measure:  Percentage of glycosylated haemoglobin
Number Analyzed 116 participants 120 participants 236 participants
7.93  (0.69) 7.92  (0.68) 7.93  (0.69)
Body weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 116 participants 120 participants 236 participants
82.2  (16.2) 85.1  (17.3) 83.7  (16.8)
1.Primary Outcome
Title Change From Baseline in HbA1c
Hide Description For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the “end of trial” data containing last available measurements.
Time Frame Week 0, week 18
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomised subjects.
Arm/Group Title Faster Aspart + Basal Basal
Hide Arm/Group Description:
During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Overall Number of Participants Analyzed 116 120
Mean (Standard Deviation)
Unit of Measure: Percentage of glycosylated haemoglobin
Baseline 7.93  (0.69) 7.92  (0.68)
Week 18 6.78  (0.92) 7.7  (0.93)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Faster Aspart + Basal, Basal
Comments Change from baseline in HbA1c after 18 weeks of treatment was analysed using a mixed-effect model for repeated measurements (MMRM) where all calculated changes in HbA1c from baseline at visits 16, 22 and 28 were included in the analysis. This model included treatment, region and strata as fixed factors, subject as random effect, baseline HbA1c as covariate and interaction between all fixed effects and visit, and between the covariate and visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -0.94
Confidence Interval (2-Sided) 95%
-1.17 to -0.72
Estimation Comments Superiority was considered confirmed if the upper bound of the two-sided 95% confidence interval (CI) for the estimated treatment difference (faster aspart+basal minus basal only), which was calculated using the FAS, was below 0%.
2.Secondary Outcome
Title Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal)
Hide Description For this endpoint the "end of trial" data containing last available measurements are presented. PPG measurements were recorded by the subjects at 2 hours after each meal (breakfast, lunch and main evening meal) as part of three 7-point profiles (SMPG) prior to the visits. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.
Time Frame After 18 weeks of randomised treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all randomised subjects. Number analysed for individual time-points = treatment wise number of subjects who contributed to analysis.
Arm/Group Title Faster Aspart + Basal Basal
Hide Arm/Group Description:
During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Overall Number of Participants Analyzed 116 120
Mean (Standard Deviation)
Unit of Measure: mmol/L
PPG breakfast; SMPG Number Analyzed 114 participants 120 participants
7.2  (1.8) 9  (2.4)
PPG lunch; SMPG Number Analyzed 114 participants 120 participants
7.1  (1.9) 9.7  (2.6)
PPG main evening meal; SMPG Number Analyzed 116 participants 120 participants
7.4  (1.9) 10.1  (2.9)
3.Secondary Outcome
Title Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal)
Hide Description For this endpoint the "end of trial" data containing last available measurements are presented. Prandial PG increment for each meal (breakfast, lunch, main evening meal) was derived from the 7-point profiles (SMPG) as the difference between the PPG value 2 hours after each meal and the PG value before each meal. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.
Time Frame After 18 weeks of randomised treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all randomised subjects. Number analysed for individual time-points = treatment wise number of subjects who contributed to analysis.
Arm/Group Title Faster Aspart + Basal Basal
Hide Arm/Group Description:
During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Overall Number of Participants Analyzed 116 120
Mean (Standard Deviation)
Unit of Measure: mmol/L
Breakfast increment; SMPG Number Analyzed 114 participants 120 participants
1.2  (1.8) 2.9  (2.4)
Lunch increment; SMPG Number Analyzed 114 participants 120 participants
0.9  (2.0) 1.8  (2.2)
Main evening meal increment; SMPG Number Analyzed 115 participants 120 participants
0.7  (1.7) 1.4  (1.9)
4.Secondary Outcome
Title Change From Baseline in Body Weight
Hide Description For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the “end of trial” data containing last available measurements.
Time Frame Week 0, week 18
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all randomised subjects.
Arm/Group Title Faster Aspart + Basal Basal
Hide Arm/Group Description:
During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Overall Number of Participants Analyzed 116 120
Mean (Standard Deviation)
Unit of Measure: Kg
Baseline 82.2  (16.2) 85.1  (17.3)
Week 18 83.9  (16.9) 85.4  (17.5)
5.Secondary Outcome
Title Number of Treatment Emergent Hypoglycaemic Episodes
Hide Description Plasma glucose (PG) was measured and recorded when a hypoglycaemic episode was suspected. All PG values ≤3.9 mmol/L (70 mg/dL) or >3.9 mmol/L (70 mg/dL) when they occurred in conjunction with hypoglycaemic symptoms were recorded by the subject. Numbers of treatment emergent hypoglycaemic episodes were recorded during 18 weeks of treatment.
Time Frame Weeks 0-18
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or its comparator.
Arm/Group Title Faster Aspart + Basal Basal
Hide Arm/Group Description:
During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Overall Number of Participants Analyzed 115 120
Measure Type: Number
Unit of Measure: Number of episodes
1908 347
6.Secondary Outcome
Title Number of Adverse Events
Hide Description All adverse events (AEs) described here refer to treatment emergent adverse events (TEAE). A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment, week 18.
Time Frame Weeks 0-18
Hide Outcome Measure Data
Hide Analysis Population Description
The SAS included all subjects receiving at least one dose of the investigational product or its comparator.
Arm/Group Title Faster Aspart + Basal Basal
Hide Arm/Group Description:
During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Overall Number of Participants Analyzed 115 120
Measure Type: Number
Unit of Measure: Number of events
123 121
Time Frame During 18 weeks of randomised treatment period + 7 days of follow-up period.
Adverse Event Reporting Description All AEs described here refer to TEAEs. The SAS included all subjects receiving at least one dose of the investigational product or its comparator.
 
Arm/Group Title Faster Aspart + Basal Basal
Hide Arm/Group Description During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day. During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
All-Cause Mortality
Faster Aspart + Basal Basal
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Faster Aspart + Basal Basal
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/115 (5.22%)      5/120 (4.17%)    
Cardiac disorders     
Cardiovascular disorder  1  1/115 (0.87%)  1 0/120 (0.00%)  0
Hepatobiliary disorders     
Cholelithiasis  1  0/115 (0.00%)  0 1/120 (0.83%)  1
Infections and infestations     
Respiratory tract infection  1  1/115 (0.87%)  1 0/120 (0.00%)  0
Injury, poisoning and procedural complications     
Carbon monoxide poisoning  1  0/115 (0.00%)  0 1/120 (0.83%)  1
Fall  1  2/115 (1.74%)  2 1/120 (0.83%)  1
Wrong drug administered  1  1/115 (0.87%)  1 0/120 (0.00%)  0
Metabolism and nutrition disorders     
Hypoglycaemia  1  2/115 (1.74%)  2 0/120 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer  1  0/115 (0.00%)  0 1/120 (0.83%)  1
Malignant respiratory tract neoplasm  1  0/115 (0.00%)  0 1/120 (0.83%)  1
Nervous system disorders     
Hypoglycaemic unconsciousness  1  0/115 (0.00%)  0 1/120 (0.83%)  1
Respiratory, thoracic and mediastinal disorders     
Lung infiltration  1  0/115 (0.00%)  0 1/120 (0.83%)  1
Vascular disorders     
Peripheral arterial occlusive disease  1  1/115 (0.87%)  1 0/120 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Faster Aspart + Basal Basal
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/115 (1.74%)      6/120 (5.00%)    
Gastrointestinal disorders     
Diarrhoea  1  2/115 (1.74%)  4 6/120 (5.00%)  6
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
At the end of the trial, one or more manuscripts for publication will be prepared collaboratively between Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for less than 60 days to protect intellectual property.
Results Point of Contact
Name/Title: Global Clinical Registry (GCR, 1452)
Organization: Novo Nordisk A/S
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT01850615     History of Changes
Other Study ID Numbers: NN1218-4049
2012-005583-10 ( EudraCT Number )
U1111-1137-6242 ( Other Identifier: WHO )
CTRI/2014/01/004289 ( Registry Identifier: Clinical Trials Registry - India (CTRI) )
First Submitted: April 17, 2013
First Posted: May 9, 2013
Results First Submitted: October 2, 2017
Results First Posted: January 17, 2018
Last Update Posted: January 29, 2019