Diabetes Mellitus, Type 2
Conditions
Brief summary
This study compares the effect on blood sugar levels of two medicines: insulin degludec and insulin glargine in people with type 2 diabetes. Participants will be treated with insulin degludec and insulin glargine during two different periods. Which treatment participants get first is decided by chance. Both medicines are approved for use in humans and available on the market. They can already be prescribed by participants' doctors. Participants will get pre-filled insulin pens to inject these insulins with. The study will last for about 41 weeks. Participants will visit the clinic 13 times and have 27 phone calls with the study doctor or study staff. At 12 of the clinic visits they will take blood samples. In order to evaluate the changes in participants' blood sugar level over time, participants will be asked to wear a small (35 millimetres (mm) x 5 mm) sensor on the back of participants' upper arm 3 times during the study. Each time participants must wear the sensor for 2 weeks. This sensor is called FreeStyle Libre Pro®. It has a very small tip which is 0.4 mm thick and is inserted 5 mm under participants' skin. Please note that participants will not be able to see the sensor readings while wearing it. The study doctor will show participants the readings when participants return to the clinic. Participants will be asked to fill in a diary in between visits. Participants will have contact with the study doctor or study staff each week. This is to adjust the dose of participants' study medicines and to ensure that participants are well. Women cannot take part if pregnant, breast-feeding or plan to become pregnant during the study period.
Interventions
DRUGInsulin degludec
Participants will receive insulin degludec U100 subcutaneous (s.c.) injection once daily for 36 weeks. Doses will be adjusted according to the fasting self-measured plasma glucose (SMPG) values. Participants earlier treated with one or more allowed oral antidiabetic drug(s) (OAD(s)), should continue their pre-trial OAD(s) treatment throughout the trial.
DRUGInsulin glargine
Participants will receive insulin glargine U100 s.c. injection once daily for 36 weeks. Doses will be adjusted according to the fasting SMPG values. Participants earlier treated with one or more allowed OAD(s), should continue their pre-trial OAD(s) treatment throughout the trial.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, age greater than or equal to 18 years at the time of signing informed consent * Diagnosed with type 2 diabetes mellitus greater than or equal to 180 days prior to the day of screening * Subjects fulfilling at least one of the below criteria: * Experienced at least one severe hypoglycaemic episode within the last year prior to screening (according to the American Diabetes Association definition, January 2018)\* * Moderate renal impairment defined as estimated glomerular filtration rate value of 30-59 mL/min/1.73 m\^2 as defined by Kidney Disease Improving Global Outcomes 2012 at screening * Known hypoglycaemic unawareness as indicated by the investigator according to Clarke's questionnaire question 8 at screening * Treated with insulin for more than 5 years * Episode of hypoglycaemia (defined a glucose alert value of 70 mg/dL (3.9 mmol/L) or less, i.e., Level 1) within the last 12 weeks prior to screening visit * Treated with any basal insulin greater than or equal to 90 days prior to the day of screening with or without any of the following anti-diabetic drugs: * Metformin * Dipeptidyl peptidase-4 inhibitor * Sodium-glucose co-transporter 2 inhibitor * Alpha-glucosidase-inhibitors (acarbose) * Thiazolidinediones * Marketed oral combination products only including the products listed above * HbA1c less than or equal to 9.5% (80 mmol/mol) at screening confirmed by central laboratory analysis * Body mass index less than or equal to 45 kg/m\^2 \*Hypoglycaemia associated with severe cognitive impairment requiring external assistance for recovery
Exclusion criteria
* Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within the past 90 days prior to the day of screening. However, intermittent bolus insulin treatment for periods of no longer than 14 days are permitted prior to the day of screening * Anticipated initiation or change in concomitant medications known to affect weight or glucose metabolism (e.g., treatment with orlistat, thyroid hormones, or corticosteroids) * Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a pharmacologically pupil-dilated fundus examination performed by an ophthalmologist or another suitably qualified health care provider within the past 90 days prior to screening or in the period between screening and run-in
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Time Spent in Glycaemic Target Range 70-180 mg/dL (3.9-10.0 mmol/L) Both Inclusive, Using Flash Glucose Monitoring (FGM) | During the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2) | The percentage of time spent in glycaemic target range was calculated as the number of recorded measurements in glycaemic target range (70-180 milligrams per deciliter \[mg/dL\] (3.9-10.0 millimoles per litre \[mmol/L\]), both inclusive) divided by the total number of recorded measurements. The endpoint is based on data recorded by FGM system. It was required that at least 70% of the planned FGM measurements during weeks 16-17 and weeks 34-35 were available for endpoint data to be included in the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time Spent in Tight Glycaemic Target Range 70-140 mg/dL (3.9-7.8 mmol/L) Both Inclusive, Using Flash Glucose Monitoring | During the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2). | The percentage of time spent in tight glycaemic target range 70-140 mg/dL (3.9-7.8 mmol/L) both inclusive, during the 2-week maintenance periods using FGM (visit 9-21 (week 16-17) and visit 37-39 (week 34-35)). |
| Time Spent in Nocturnal Glycaemic Target Range 70-140 mg/dL (3.9-7.8 mmol/L) Both Inclusive, in the Nocturnal Period (00:01 am - 05:59 am Both Inclusive) Using Flash Glucose Monitoring | During the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2). | Percentage of time spent in nocturnal glycaemic target range 70-140 mg/dL (3.9-7.8 mmol/L) both inclusive, in the nocturnal period (00:01 am - 05:59 am both inclusive) during the 2-week maintenance periods using FGM (visit 19-21 (week 16-17) and visit 37-39 (week 34-35)). |
| Level of Glycated Haemoglobin (HbA1c) - Percentage | After the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2). | Level of HbA1c after two weeks of maintenance periods (Visit 19-21 (week 16-17) and Visit 37-39 (week 34-35)). |
| Level of Glycated Haemoglobin (HbA1c) - mmol/Mol | After the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2). | Level of HbA1c after two weeks of maintenance periods (Visit 19-21 (week 16-17) and Visit 37-39 (week 34-35)). |
| Mean Glucose Levels Using Flash Glucose Monitoring (FGM) | During the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2). | Mean glucose levels (mmol/L) during the 2-week maintenance periods using FGM (visit 19-21 (week 16-17) and visit 37-39 (week 34-35)). |
Countries
Canada, Poland, Puerto Rico, Slovakia, South Africa, United States
Participant flow
Recruitment details
The trial was conducted in 5 countries as follows: Canada: 10 sites, Poland: 5 sites, Slovakia: 10 sites, South Africa: 7 sites, United States of America: 34 sites
Pre-assignment details
This was a cross-over trial. The trial included a 2-week run-in period (which was after the screening visit) for eligibility assessment in regard to adherence to FGM requirements. The participants were randomized into one of two treatment sequences.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Participants were to receive subcutaneous (s.c.) injection of Insulin degludec 100U/mL once daily followed by a s.c. injection of Insulin glargine 100U/mL once daily in 2 treatment periods with or without oral anti-diabetic drugs using flash glucose monitoring. Each treatment period consisted of a 16-week titration period followed by a 2-week maintenance period. | 498 |
| Total | 498 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Death | 0 | 1 |
| Treatment Period 1 | Lost to Follow-up | 2 | 2 |
| Treatment Period 1 | Physician Decision | 5 | 2 |
| Treatment Period 1 | Withdrawal by Subject | 7 | 3 |
| Treatment Period 2 | Physician Decision | 4 | 1 |
| Treatment Period 2 | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 62.8 Years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 100 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 398 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants |
| Race/Ethnicity, Customized Asian | 23 Participants |
| Race/Ethnicity, Customized Black or African American | 39 Participants |
| Race/Ethnicity, Customized Other | 19 Participants |
| Race/Ethnicity, Customized White | 415 Participants |
| Sex: Female, Male Female | 259 Participants |
| Sex: Female, Male Male | 239 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 490 | 1 / 484 |
| other Total, other adverse events | 0 / 490 | 0 / 484 |
| serious Total, serious adverse events | 26 / 490 | 23 / 484 |
Outcome results
Primary
Percentage of Time Spent in Glycaemic Target Range 70-180 mg/dL (3.9-10.0 mmol/L) Both Inclusive, Using Flash Glucose Monitoring (FGM)
The percentage of time spent in glycaemic target range was calculated as the number of recorded measurements in glycaemic target range (70-180 milligrams per deciliter \[mg/dL\] (3.9-10.0 millimoles per litre \[mmol/L\]), both inclusive) divided by the total number of recorded measurements. The endpoint is based on data recorded by FGM system. It was required that at least 70% of the planned FGM measurements during weeks 16-17 and weeks 34-35 were available for endpoint data to be included in the analysis.
Time frame: During the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2)
Population: Per protocol (PP) analysis set - The PP analysis set consisted of subjects that stayed on assigned treatment until and completed FGM assessment at visits 21 and 39 respectively.~Complete FGM assessment was specified as subjects having at least 70% of 2 weeks FGM measurements per maintenance period (2 \* 960 measurements).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec 100U/mL | Percentage of Time Spent in Glycaemic Target Range 70-180 mg/dL (3.9-10.0 mmol/L) Both Inclusive, Using Flash Glucose Monitoring (FGM) | 72.11 Percentage of Time | Standard Error 0.74 |
| Insulin Glargine 100U/mL | Percentage of Time Spent in Glycaemic Target Range 70-180 mg/dL (3.9-10.0 mmol/L) Both Inclusive, Using Flash Glucose Monitoring (FGM) | 70.68 Percentage of Time | Standard Error 0.74 |
p-value: 0.032195% CI: [0.12, 2.74]t-test, 2 sided
95% CI: [0.12, 2.74]
Secondary
Level of Glycated Haemoglobin (HbA1c) - mmol/Mol
Level of HbA1c after two weeks of maintenance periods (Visit 19-21 (week 16-17) and Visit 37-39 (week 34-35)).
Time frame: After the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2).
Population: Per protocol (PP) analysis set - The PP analysis set consisted of subjects that stayed on assigned treatment until and completed FGM assessment at visits 21 and 39 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec 100U/mL | Level of Glycated Haemoglobin (HbA1c) - mmol/Mol | 54.10 millimoles per mole (mmol/mol) | Standard Error 0.42 |
| Insulin Glargine 100U/mL | Level of Glycated Haemoglobin (HbA1c) - mmol/Mol | 54.78 millimoles per mole (mmol/mol) | Standard Error 0.42 |
Secondary
Level of Glycated Haemoglobin (HbA1c) - Percentage
Level of HbA1c after two weeks of maintenance periods (Visit 19-21 (week 16-17) and Visit 37-39 (week 34-35)).
Time frame: After the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2).
Population: Per protocol (PP) analysis set - The PP analysis set consisted of subjects that stayed on assigned treatment until and completed FGM assessment at visits 21 and 39 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec 100U/mL | Level of Glycated Haemoglobin (HbA1c) - Percentage | 7.10 Percentage of glycated haemoglobin | Standard Error 0.04 |
| Insulin Glargine 100U/mL | Level of Glycated Haemoglobin (HbA1c) - Percentage | 7.16 Percentage of glycated haemoglobin | Standard Error 0.04 |
Secondary
Mean Glucose Levels Using Flash Glucose Monitoring (FGM)
Mean glucose levels (mmol/L) during the 2-week maintenance periods using FGM (visit 19-21 (week 16-17) and visit 37-39 (week 34-35)).
Time frame: During the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2).
Population: Per protocol (PP) analysis set - The PP analysis set consisted of subjects that stayed on assigned treatment until and completed FGM assessment at visits 21 and 39 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec 100U/mL | Mean Glucose Levels Using Flash Glucose Monitoring (FGM) | 7.57 mmol/L | Standard Error 0.08 |
| Insulin Glargine 100U/mL | Mean Glucose Levels Using Flash Glucose Monitoring (FGM) | 7.61 mmol/L | Standard Error 0.08 |
Secondary
Time Spent in Nocturnal Glycaemic Target Range 70-140 mg/dL (3.9-7.8 mmol/L) Both Inclusive, in the Nocturnal Period (00:01 am - 05:59 am Both Inclusive) Using Flash Glucose Monitoring
Percentage of time spent in nocturnal glycaemic target range 70-140 mg/dL (3.9-7.8 mmol/L) both inclusive, in the nocturnal period (00:01 am - 05:59 am both inclusive) during the 2-week maintenance periods using FGM (visit 19-21 (week 16-17) and visit 37-39 (week 34-35)).
Time frame: During the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2).
Population: Per protocol (PP) analysis set - The PP analysis set consisted of subjects that stayed on assigned treatment until and completed FGM assessment at visits 21 and 39 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec 100U/mL | Time Spent in Nocturnal Glycaemic Target Range 70-140 mg/dL (3.9-7.8 mmol/L) Both Inclusive, in the Nocturnal Period (00:01 am - 05:59 am Both Inclusive) Using Flash Glucose Monitoring | 15.15 Percentage of Time | Standard Error 0.26 |
| Insulin Glargine 100U/mL | Time Spent in Nocturnal Glycaemic Target Range 70-140 mg/dL (3.9-7.8 mmol/L) Both Inclusive, in the Nocturnal Period (00:01 am - 05:59 am Both Inclusive) Using Flash Glucose Monitoring | 14.91 Percentage of Time | Standard Error 0.26 |
Secondary
Time Spent in Tight Glycaemic Target Range 70-140 mg/dL (3.9-7.8 mmol/L) Both Inclusive, Using Flash Glucose Monitoring
The percentage of time spent in tight glycaemic target range 70-140 mg/dL (3.9-7.8 mmol/L) both inclusive, during the 2-week maintenance periods using FGM (visit 9-21 (week 16-17) and visit 37-39 (week 34-35)).
Time frame: During the 2-week maintenance period: weeks 16-17 (period-1) and weeks 34-35 (period-2).
Population: Per protocol (PP) analysis set - The PP analysis set consisted of subjects that stayed on assigned treatment until and completed FGM assessment at visits 21 and 39 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec 100U/mL | Time Spent in Tight Glycaemic Target Range 70-140 mg/dL (3.9-7.8 mmol/L) Both Inclusive, Using Flash Glucose Monitoring | 52.97 Percentage of Time | Standard Error 0.82 |
| Insulin Glargine 100U/mL | Time Spent in Tight Glycaemic Target Range 70-140 mg/dL (3.9-7.8 mmol/L) Both Inclusive, Using Flash Glucose Monitoring | 51.45 Percentage of Time | Standard Error 0.82 |