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

Phase 3

Completed

• Conditions: Diabetes Mellitus, Type 2; Diabetes
• Interventions: Drug: insulin degludec/liraglutide; Drug: insulin glargine

• Registration Number: NCT02501161
• Lead Sponsor: Novo Nordisk A/S

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-07-15
• Study First Submitted QC: 2015-07-15
• Study First Posted: 2015-07-17
• Study Start: 2016-01-31
• Primary Completion: 2018-10-03
• Study Completion: 2018-10-03
• Results First Submitted: 2019-10-03
• Status Verified: 2019-11
• Results First Submitted QC: 2019-11-08
• Last Update Submitted: 2019-11-08
• Results First Posted: 2019-11-27
• Last Update Posted: 2019-11-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1012

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)

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Insulin degludec/liraglutide QD + OAD(s)	insulin degludec/liraglutide	-
insulin glargine QD + OAD(s)	insulin glargine	-

Primary Outcome Measures

Name	Time	Method
Time From Randomisation to Inadequate Glycaemic Control and Need for Treatment Intensification	Weeks 0-104 + 7 days follow-up-1 + 30 days follow-up-2	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.

Secondary Outcome Measures

Name	Time	Method
Insulin Dose	Week 26, week 104	Insulin dose after 26 and 104 weeks of treatment is presented.
Participants Who Achieved (Yes/no): HbA1c <7.0%	Week 26, week 104	Percentage of participants who achieved (yes/no) HbA1c \<7.0% at week 26 and week 104 is presented.
Participants Who Achieved (Yes/no): HbA1c ≤6.5%	Week 26, week 104	Percentage of participants who achieved (yes/no) HbA1c ≤6.5% at week 26 and week 104 is presented.
Time From Randomisation to HbA1c >6.5% at 2 Consecutive Visits	Weeks 0-104 + 7 days follow-up-1 + 30 days follow-up-2	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.
Change in HbA1c	Week 0, week 26	Change in HbA1c from baseline (week 0) to week 26 is presented.
Participants Who Achieved (Yes/no): HbA1c <7.0% Without Weight Gain	Week 26, week 104	Percentage of participants who achieved (yes/no) HbA1c \<7.0% without weight gain at week 26 and week 104 is presented.
Participants Who Achieved (Yes/no): HbA1c ≤6.5% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes	Week 26, week 104	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.
Participants Who Achieved (Yes/no): HbA1c ≤6.5% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes and Without Weight Gain	Week 26, week 104	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.
Change in Body Weight	Week 0, week 26, week 104	Change in body weight from baseline (week 0) to week 26 and week 104 is presented.
Change in SMPG-mean 9-point Profile	Week 0, week 26, week 104	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.
Change in SMPG-mean Postprandial Increment Over All Meals	Week 0, week 26, week 104	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.
Change in Blood Pressure (Systolic and Diastolic)	Week 0, week 26, week 104	Change in blood pressure (systolic and diastolic) from baseline (week 0) to week 26 and week 104 is presented.
Change in Fasting C-peptide	Week 0, week 26, week 104	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.
Change in Fasting Human Insulin	Week 0, week 26, week 104	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.
Change in Fasting Total Cholesterol	Week 0, week 26, week 104	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.
Change in Fasting LDL-cholesterol	Week 0, week 26, week 104	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.
Change in Fasting HDL-cholesterol	Week 0, week 26, week 104	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.
Change in Fasting VLDL-cholesterol	Week 0, week 26, week 104	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.
Change in Fasting Triglycerides	Week 0, week 26, week 104	Change in fasting triglycerides (measured as mmol/L) from baseline (week 0) to week 26 and week 104 is presented as ratio to baseline.
Change in Fasting Free Fatty Acids	Week 0, week 26, week 104	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.
Number of Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 26 Weeks of Treatment	Weeks 0-26	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.
Number of Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 104 Weeks of Treatment	Weeks 0-104	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.
Number of Treatment Emergent Hypoglycaemic Episodes During 26 Weeks of Treatment	Weeks 0-26	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.
Number of Treatment Emergent Hypoglycaemic Episodes During 104 Weeks of Treatment	Weeks 0-104	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.
Number of Treatment-emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 26 Weeks of Treatment	Weeks 0-26	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.
Number of Treatment-emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 104 Weeks of Treatment	Weeks 0-104	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.
Number of TEAEs During 26 Weeks of Treatment	Weeks 0-26	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.
Number of TEAEs During 104 Weeks of Treatment	Week 0 to week 104	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.
Eye Examination Category	Baseline (within 12 weeks prior to week 0), week 104	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.
ECG Evaluation	Baseline (within 2 weeks prior to week 0), week 104	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.
Change in Urine Albumin/Creatinine Ratio	Week 0, week 104	Change in urine albumin/creatinine ratio from baseline (week 0) to week 104 is presented.
Change in Pulse Rate	Week 0, week 26, week 104	Change in pulse rate from baseline (week 0) to week 26 and week 104 is presented.
Change in Biochemistry Parameter- Creatinine, Total Bilirubin	Week 0, week 26, week 104	Change in biochemistry parameter- creatinine, total bilirubin from baseline (week 0) to week 26 and week 104 is presented.
Change in Biochemistry Parameter- Albumin	Week 0, week 26, week 104	Change in biochemistry parameter- albumin from baseline (week 0) to week 26 and week 104 is presented.
Change in Biochemistry Parameters- ALP, ALT, AST, Lipase and Amylase	Week 0, week 26, week 104	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.
Change in Biochemistry Parameter- Sodium, Potassium and Calcium	Week 0, week 26, week 104	Change in sodium, potassium and calcium from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Haemoglobin	Week 0, week 26, week 104	Change in haemoglobin from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Haematocrit	Week 0, week 26, week 104	Change in haematocrit from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Erythrocytes	Week 0, week 26, week 104	Change in erythrocytes from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Thrombocytes and Leukocytes	Week 0, week 26, week 104	Change in thrombocytes and leukocytes from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Eosinophils	Week 0, week 26, week 104	Change in eosinophils from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Neutrophils	Week 0, week 26, week 104	Change in neutrophils from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Basophils	Week 0, week 26, week 104	Change in basophils from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Monocytes	Week 0, week 26, week 104	Change in monocytes from baseline (week 0) to week 26 and week 104 is presented.
Change in Haematological Parameter- Lymphocytes	Week 0, week 26, week 104	Change in lymphocytes from baseline (week 0) to week 26 and week 104 is presented.
Change in Calcitonin	Week 0, week 26, week 104	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.
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)	Week 0, week 26, week 104	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.
Change in TRIM-D	Week 0, week 26, week 104	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.
Participants Who Achieved (Yes/no): HbA1c <7.0% Without Treatment-emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes	Week 26, week 104	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.
Participants Who Achieved (Yes/no): HbA1c < 7.0% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes and Without Weight Gain	Week 26, week 104	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.
Participants Who Achieved (Yes/no): HbA1c ≤6.5% Without Weight Gain	Week 26, week 104	Percentage of participants who achieved (yes/no) HbA1c ≤6.5% without weight gain at week 26 and week 104 is presented.
Change in FPG	Week 0, week 26, week 104	Change in fasting plasma glucose (FPG) from baseline (week 0) to week 26 and week 104 is presented.
SMPG-9-point Profile (Individual Points in the Profile)	Week 26, week 104	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.

Trial Locations

Locations (1)

Novo Nordisk Investigational Site; 🇬🇧 Wolverhampton, United Kingdom