A 104 Week Clinical Trial Comparing Long Term Glycaemic Control of Insulin Degludec/Liraglutide (IDegLira) Versus Insulin Glargine Therapy in Subjects With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This trial is conducted in Africa, Asia, Europe, North America and South America. The purpose is to compare long-term glycaemic control of insulin degludec/liraglutide (IDegLira) versus insulin glargine (IGlar) in insulin naïve subjects with type 2 diabetes mellitus inadequately controlled with oral anti diabetics.

Official Title
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A Clinical Trial Comparing Long Term Glycaemic Control of Insulin Degludec/Liraglutide (IDegLira) Versus Insulin Glargine Therapy in Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: insulin degludec/liraglutide
* Drug: insulin glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age greater than or equal to 18 years at the time of signing informed consent Subjects diagnosed with type 2 diabetes mellitus HbA1c 7.0-11.0% (both inclusive) (53-97 mmol/mol) by central laboratory analysis Body mass index greater than or equal to 20 kg/m^2 Insulin naïve subjects; however short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as is prior insulin treatment for gestational diabetes Stable daily dose(s) including any of the following antidiabetic drug(s)/regimens within 90 days prior to the day of screening: a) Biguanides (metformin greater than or equal to 1500 mg or maximum tolerated dose documented in the subject medical record), b) Other OAD(s) allowed: sulphonylurea, glinides, pioglitazone, and DPP4-inhibitors (greater than or equal to half of the maximum approved dose according to local label or maximum tolerated dose as documented in subjects medical record) Exclusion Criteria: Screening calcitonin greater than or equal to 50 ng/L Renal impairment estimated Glomerular Filtration Rate (eGFR) less than 60 ml/min/1.73 m2 as per CKD-EPI value to be defined as listed in the classification CKD-EPI using IDMS for serum creatinine measurement on the day of screening Impaired liver function, defined as ALAT or ASAT greater than or equal to 2.5 times upper limit of normal Family or personal history of Multiple Endocrine Neoplasia Type 2 or Medullary Thyroid Carcinoma History of pancreatitis (acute or chronic) Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 days before the day of screening Anticipated initiation or change in concomitant medications for more than 14 consecutive days or on a frequent basis known to affect weight or glucose metabolism (e.g. orlistat, thyroid hormones, corticosteroids)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin degludec/liraglutide QD + OAD(s)<br> | Drug: insulin degludec/liraglutide<br>* Injected subcutaneously (under the skin) once daily for 104 weeks. Dose individually adjusted.<br>|
| Active Comparator: insulin glargine QD + OAD(s)<br> | Drug: insulin glargine<br>* Injected subcutaneously (under the skin) once daily for 104 weeks. Dose individually adjusted.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Randomisation to Inadequate Glycaemic Control and Need for Treatment Intensification | Inadequate glycaemic control and need for treatment intensification was defined as a glycosylated haemoglobin (HbA1c) of 7.0% or greater at 2 consecutive visits from week 26, including week 26 if HbA1c was greater than or equal to 7% at week 12. Time from randomisation to inadequate glycaemic control and need for treatment intensification was analysed using a stratified log-rank test where treatment, baseline HbA1c group and previous OAD treatment were included as strata in the model. The variable baseline HbA1c group was a dichotomised baseline HbA1c variable with 2 categories: HbA1c < 8.5% or HbA1c ≥ 8.5% and the variable previous OAD treatment was a categorical variable with 2 categories: SU ± OAD(s) (SU users) or OAD(s) (Non-SU users). 25%, median (50%) and 75% percentiles for the cumulative distribution function were obtained from the Kaplan-Meier survival function. | Weeks 0-104 + 7 days follow-up-1 + 30 days follow-up-2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Randomisation to HbA1c >6.5% at 2 Consecutive Visits | Time to HbA1c > 6.5% at 2 consecutive visits is defined as time from randomization to HbA1c > 6.5% at 2 consecutive planned scheduled visits from week 26 (including week 26 if HbA1c was > 6.5% at week 12). Time from randomisation to HbA1c >6.5% at 2 consecutive visits was analysed using a stratified log-rank test where treatment, baseline HbA1c group and previous OAD treatment were included as strata in the model. The variable baseline HbA1c group was a dichotomised baseline HbA1c variable with 2 categories: HbA1c < 8.5% or HbA1c ≥ 8.5% and the variable previous OAD treatment was a categorical variable with 2 categories: SU ± OAD(s) (SU users) or OAD(s) (Non-SU users). 25%, median (50%) and 75% percentiles for the cumulative distribution function were obtained from the Kaplan-Meier survival function. | Weeks 0-104 + 7 days follow-up-1 + 30 days follow-up-2 | 
| Change in HbA1c | Change in HbA1c from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Body Weight | Change in body weight from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Insulin Dose | Insulin dose after 26 and 104 weeks of treatment is presented. | Week 26, week 104 | 
| Participants Who Achieved (Yes/no): HbA1c <7.0% | Percentage of participants who achieved (yes/no) HbA1c <7.0% at week 26 and week 104 is presented. | Week 26, week 104 | 
| Participants Who Achieved (Yes/no): HbA1c <7.0% Without Weight Gain | Percentage of participants who achieved (yes/no) HbA1c <7.0% without weight gain at week 26 and week 104 is presented. | Week 26, week 104 | 
| Participants Who Achieved (Yes/no): HbA1c <7.0% Without Treatment-emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Severe or BG confirmed symptomatic hypoglycaemia was defined as an episode that was severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Percentage of participants who achieved (yes/no) HbA1c <7.0% without treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes at week 26 and week 104 is presented. | Week 26, week 104 | 
| Participants Who Achieved (Yes/no): HbA1c < 7.0% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes and Without Weight Gain | Severe or BG confirmed symptomatic hypoglycaemia was defined as an episode that was severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Percentage of participants who achieved (yes/no) HbA1c <7.0% without treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes and without weight gain at week 26 and week 104 is presented. | Week 26, week 104 | 
| Participants Who Achieved (Yes/no): HbA1c ≤6.5% | Percentage of participants who achieved (yes/no) HbA1c ≤6.5% at week 26 and week 104 is presented. | Week 26, week 104 | 
| Participants Who Achieved (Yes/no): HbA1c ≤6.5% Without Weight Gain | Percentage of participants who achieved (yes/no) HbA1c ≤6.5% without weight gain at week 26 and week 104 is presented. | Week 26, week 104 | 
| Participants Who Achieved (Yes/no): HbA1c ≤6.5% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Severe or BG confirmed symptomatic hypoglycaemia is defined as an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Percentage of participants who achieved (yes/no) HbA1c ≤6.5% without treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes at week 26 and week 104 is presented. | Week 26, week 104 | 
| Participants Who Achieved (Yes/no): HbA1c ≤6.5% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes and Without Weight Gain | Severe or BG confirmed symptomatic hypoglycaemia is defined as an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Percentage of participants who achieved (yes/no) HbA1c ≤6.5% without treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes and without weight gain at week 26 and week 104 is presented. | Week 26, week 104 | 
| Change in FPG | Change in fasting plasma glucose (FPG) from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| SMPG-9-point Profile (Individual Points in the Profile) | Participants measured plasma glucose values using the blood glucose meter at 9 time points: before breakfast, 90 min after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 min after start of dinner, bedtime, at 4:00 am and before breakfast the following day. Self-measured plasma glucose (SMPG)-9-point profile (individual points in the profile) at week 26 and week 104 is presented. | Week 26, week 104 | 
| Change in SMPG-mean 9-point Profile | Participants measured plasma glucose values using the blood glucose meter at 9 time points: before breakfast, 90 min after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 min after start of dinner, bedtime, at 4:00 am and before breakfast the following day. Change in SMPG-mean 9-point profile from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in SMPG-mean Postprandial Increment Over All Meals | Participants measured plasma glucose values using the blood glucose meter at 9 time points: before breakfast, 90 min after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 min after start of dinner, bedtime, at 4:00 am and before breakfast the following day. Change in SMPG-mean postprandial increment over all meals from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Blood Pressure (Systolic and Diastolic) | Change in blood pressure (systolic and diastolic) from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Fasting C-peptide | Change in fasting C-peptide (measured in nanomoles per liter [nmol/L]) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline. | Week 0, week 26, week 104 | 
| Change in Fasting Human Insulin | Change in fasting human insulin (measured in picomoles per liter [pmol/L]) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline. | Week 0, week 26, week 104 | 
| Change in Fasting Total Cholesterol | Change in fasting total cholesterol (measured in mmol/L) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline. | Week 0, week 26, week 104 | 
| Change in Fasting LDL-cholesterol | Change in fasting low density lipoprotein (LDL)-cholesterol (measured in mmol/L) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline. | Week 0, week 26, week 104 | 
| Change in Fasting HDL-cholesterol | Change in fasting high density lipoprotein (HDL)- cholesterol (measured in mmol/L) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline. | Week 0, week 26, week 104 | 
| Change in Fasting VLDL-cholesterol | Change in fasting very low density lipoprotein (VLDL)-cholesterol (measured in mmol/L) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline. | Week 0, week 26, week 104 | 
| Change in Fasting Triglycerides | Change in fasting triglycerides (measured as mmol/L) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline. | Week 0, week 26, week 104 | 
| Change in Fasting Free Fatty Acids | Change in fasting free fatty acids (measured as mmol/L) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline. | Week 0, week 26, week 104 | 
| Number of Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 26 Weeks of Treatment | Severe or BG confirmed symptomatic hypoglycaemia is defined as an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 26 weeks of treatment is presented. | Weeks 0-26 | 
| Number of Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 104 Weeks of Treatment | Severe or BG confirmed symptomatic hypoglycaemia is defined as an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 104 weeks of treatment is presented. | Weeks 0-104 | 
| Number of Treatment Emergent Hypoglycaemic Episodes During 26 Weeks of Treatment | Hypoglycaemic episodes (SMPG value ≤3.9 mmol/L (70 mg/dL)) were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent hypoglycaemic episodes according to ADA during 26 weeks of treatment is presented. | Weeks 0-26 | 
| Number of Treatment Emergent Hypoglycaemic Episodes During 104 Weeks of Treatment | Hypoglycaemic episodes (SMPG value ≤3.9 mmol/L (70 mg/dL)) were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment emergent hypoglycaemic episodes according to ADA during 104 weeks of treatment is presented. | Weeks 0-104 | 
| Number of Treatment-emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 26 Weeks of Treatment | Severe or BG confirmed symptomatic hypoglycaemia is defined as an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Nocturnal hypoglycaemic episodes were episodes occurring between 00:01 and 05.59 both inclusive. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes during 26 weeks of treatment is presented. | Weeks 0-26 | 
| Number of Treatment-emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 104 Weeks of Treatment | Severe or BG confirmed symptomatic hypoglycaemia is defined as an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Nocturnal hypoglycaemic episodes were episodes occurring between 00:01 and 05.59 both inclusive. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes during 104 weeks of treatment is presented. | Weeks 0-104 | 
| Number of TEAEs During 26 Weeks of Treatment | An adverse event is any untoward medical occurrence in a participant administered a product, and which does not necessarily have a causal relationship with this treatment. A treatment emergent adverse event (TEAE) was defined as an adverse event that had onset date on or after the first day of exposure to trial product and no later than 7 days after the last day of trial product. If the event had onset date before the first day of exposure on trial product and increased in severity during the treatment period and until 7 days after the last drug date, then this event was also considered as a TEAE. Number of TEAEs during 26 weeks of treatment is presented. | Weeks 0-26 | 
| Number of TEAEs During 104 Weeks of Treatment | An adverse event is any untoward medical occurrence in a participant administered a product, and which does not necessarily have a causal relationship with this treatment. A TEAE was defined as an adverse event that had onset date on or after the first day of exposure to trial product and no later than 7 days after the last day of trial product. If the event had onset date before the first day of exposure on trial product and increased in severity during the treatment period and until 7 days after the last drug date, then this event was also considered as a TEAE. Number of TEAEs during 104 weeks of treatment is presented. | Week 0 to week 104 | 
| Eye Examination Category | Fundus photography or a dilated fundoscopy was performed at baseline (within 12 weeks prior to week 0) and week 104. The investigator interpreted each eye's (left and right) results and categorised them as: normal, abnormal not clinically significant (NCS) or abnormal clinically significant (CS). Number of participants in each category at baseline and week 104 were presented. | Baseline (within 12 weeks prior to week 0), week 104 | 
| ECG Evaluation | The electrocardiogram (ECG) was assessed at baseline (within 2 weeks prior to week 0) and week 104. The investigator interpreted the results and categorised them as: normal, abnormal NCS or abnormal CS. Number of participants in each ECG category at baseline and week 104 are presented. | Baseline (within 2 weeks prior to week 0), week 104 | 
| Change in Urine Albumin/Creatinine Ratio | Change in urine albumin/creatinine ratio from baseline (week 0) to week 104 is presented. | Week 0, week 104 | 
| Change in Pulse Rate | Change in pulse rate from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Biochemistry Parameter- Creatinine, Total Bilirubin | Change in biochemistry parameter- creatinine, total bilirubin from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Biochemistry Parameter- Albumin | Change in biochemistry parameter- albumin from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Biochemistry Parameters- ALP, ALT, AST, Lipase and Amylase | Change in biochemistry parameters- alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipase and amylase from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Biochemistry Parameter- Sodium, Potassium and Calcium | Change in sodium, potassium and calcium from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Haemoglobin | Change in haemoglobin from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Haematocrit | Change in haematocrit from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Erythrocytes | Change in erythrocytes from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Thrombocytes and Leukocytes | Change in thrombocytes and leukocytes from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Eosinophils | Change in eosinophils from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Neutrophils | Change in neutrophils from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Basophils | Change in basophils from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Monocytes | Change in monocytes from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Haematological Parameter- Lymphocytes | Change in lymphocytes from baseline (week 0) to week 26 and week 104 is presented. | Week 0, week 26, week 104 | 
| Change in Calcitonin | The number of participants who reported low, normal and high levels of calcitonin in relation to reference ranges at baseline (week 0), week 26 and week 104 are presented. | Week 0, week 26, week 104 | 
| Change in Short Form Health Survey Version 2.0 (SF-36v2™, Acute Version) Health Survey: Scores From the 8 Domains and Summaries of the Physical Component Score (PCS) and the Mental Component Score (MCS) | SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The scores 0-100 (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. Change from baseline in the sub-domain scores and component summary (PCS and MCS) scores are presented. A positive change score indicates an improvement since baseline. | Week 0, week 26, week 104 | 
| Change in TRIM-D | Treatment related impact measures-diabetes (TRIM-D) was developed according to the FDA guidance from 2009 on development of new PRO measures. The questionnaire consists of 5 sub-domains, which are scored according to a 1-5 point scale with a higher score indicating a better health state (less negative impact). Sub-domain scores are calculated by summing across items in the same sub-domain, and the total score is calculated by summing scores from all the sub-domains. The highest possible summed score within a sub-domain ranges from 20 (compliance sub-domain) to 40 (psychological health sub-domain) points and the highest possible total score is 140 points. Change in TRIM-D total score from baseline (week 0) to week 26 and week 104 is presented. A positive change score indicates an improvement since baseline. | Week 0, week 26, week 104 |