A Research Study of How Overdosing of a New Once Weekly Medicine NNC0148-0287 C (Insulin 287) Influences the Blood Sugar Level in People With Type 2 Diabetes

Study Overview
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Brief Summary
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This study is comparing the effect of a long-acting insulin analogue (insulin 287) with insulin glargine (Lantus®) in subjects with type 2 diabetes. In addition, the study is looking at symptoms of low blood sugar, awareness of low blood sugar and the time and amount of glucose needed to recover from low blood sugar after injecting 2 and 3 times the basal dose of insulin 287 and glargine. The purpose of the study is to make a once-weekly injectable basal insulin treatment for people with type 2 diabetes. Participants will get insulin 287 as well as insulin glargine - which treatment any participant gets first is decided by chance. Insulin 287 is a new medicine; insulin glargine can already be prescribed. The study medicines will be in a pen, and must be injected with a needle in the thigh once per day (insulin glargine) or once per week (insulin 287). The study will last for minimum 3 months and up to approximately 6 months. Participants will have 21 clinic visits and at least 2 phone calls with the study doctor. The participants' health will be monitored carefully and blood samples will be taken at the clinic visits.

Official Title
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A Trial Investigating the Hypoglycaemic Response to Overdosing of NNC0148-0287 C (Insulin 287) in Subjects With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: insulin icodec
* Drug: Insulin glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged between 18 and 72 years (both inclusive) at the time of signing informed consent. Body mass index between 18.5 and 37.9 kg/m^2 (both inclusive). Diagnosed with type 2 diabetes mellitus greater than or equal to 180 days prior to the day of screening. Glycosylated haemoglobin type A1c (HbA1c) less than or equal to 9.0% (less than or equal to 74 mmol/mol) at screening. Current total daily insulin treatment between 0.2 and 1.0 U/kg/day (both inclusive). Exclusion Criteria: Known or suspected hypersensitivity to trial products or related products. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method. Presence or history of any clinically relevant respiratory, metabolic, renal, hepatic, gastrointestinal, endocrinological conditions (except conditions associated with diabetes mellitus).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 72 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin 287 followed by insulin glargine<br>Run-in period (3 to 28 days): Once daily insulin glargine treatment with or without any usual metformin treatment. After run-in, participants will receive insulin 287 once a week (OW) for 6 weeks. After insulin 287 treatment, participants will receive insulin glargine U100 OD for 12 days. | Drug: insulin icodec<br>* Participants will receive subcutaneous (s.c.) injections of insulin 287 OW for 6 weeks<br>* Other names: Insulin 287;Drug: Insulin glargine<br>* Participants will receive daily s.c. injections of insulin glargine U100 for 12 days<br>|
| Active Comparator: Insulin glargine followed by insulin 287<br>Run-in period (3 to 28 days): Once daily insulin glargine treatment with or without any usual metformin treatment. After run-in, participants will receive insulin glargine U100 OD for 12 days. After insulin glargine treatment, participants will receive insulin 287 OW for 6 weeks. | Drug: insulin icodec<br>* Participants will receive subcutaneous (s.c.) injections of insulin 287 OW for 6 weeks<br>* Other names: Insulin 287;Drug: Insulin glargine<br>* Participants will receive daily s.c. injections of insulin glargine U100 for 12 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically significant hypoglycaemia (Double dose): Clinically significant hypoglycaemia (Plasma glucose [PG] less than 3.0 mmol/L [54 mg/dL]) after 2 times the individualised optimal basal dose of insulin | Yes/No Blood sugar lower than 3.0 mmol/L (54 mg/dL) after receiving a double dose of basal insulin Number of subjects experiencing an event is to be reported | From start of hypoglycaemia induction after 2 times the individualised optimal basal dose of insulin (day 17 for insulin 287, day 4 for insulin glargine) until termination of the clamp the following day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PG (nadir) - PG concentration at nadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in mmol/L Minimum blood sugar level achieved after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| t (decline, PG 5.5 mmol/L - PG 3.0 mmol/L) - Time from start of hypoglycaemia induction until a PG concentration of 3.0 mmol/L (54 mg/dL) is reached after 2 and 3 times the individualised optimal basal dose of insulin | Measured in hours Time from when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until blood sugar is 3.0 mmol/L (54 mg/dL) after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| t (decline, PG 5.5 mmol/L - PG nadir) - Time from start of hypoglycaemia induction until PGnadir is reached after 2 and 3 times the individualised optimal basal dose of insulin | Measured in hours Time from when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| t (recovery, PG nadir - PG 5.5 mmol/L) - Time to increase from PGnadir to a PG concentration of 5.5 mmol/L (100 mg/dL) after 2 and 3 times the individualised optimal basal dose of insulin | Measured in hours Time from when blood sugar is at a minimum level until blood sugar is normal [5.5 mmol/L (100 mg/dL)] during recovery from low blood sugar after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| C (glucagon, PG nadir) - Plasma glucagon concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in pg/mL Blood level of the glucagon hormone at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| C (adrenaline, PG nadir) - Plasma adrenaline concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in pg/mL Blood level of the adrenaline hormone at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| C (noradrenaline, PG nadir) - Plasma noradrenaline concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in pg/mL Blood level of the noradrenaline hormone at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| C (growth hormone [GH], PG nadir) - Serum growth hormone concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in ng/mL Blood level of GH at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| C (cortisol, PG nadir) - Serum cortisol concentration at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in ng/mL Blood level of the cortisol hormone at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Pulse (PG 5.5 mmol/L - PG nadir) - Change in pulse rate from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in beats/min Change in pulse from the time point when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Diastolic blood pressure (DBP) (PG 5.5 mmol/L - PG nadir) - Change in diastolic blood pressure from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in mmHg Change in DBP from the time point when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Systolic blood pressure (SBP) (PG 5.5 mmol/L - PG nadir) - Change in systolic blood pressure from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in mmHg Change in SBP from the time point when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Digit Symbol Substitution Test (DSST) (PG 5.5 mmol/L - PG nadir) - Change in DSST score from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Number of correct responses Change in performance in the DSST (a cognitive ability test) from the time point when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Four-Choice Reaction Time (4CRT) (reaction 4CRT) (PG 5.5 mmol/L - PG nadir) - Change in 4CRT performance from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in msec Change in reaction time in the 4CRT test (a cognitive ability test) from the time point when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| 4CRT (% correct answers) (PG 5.5 mmol/L - PG nadir) - Change in 4CRT performance (% correct answers) from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in %-points Change in the percentage correct answers in the 4CRT test (a cognitive ability test) from the time point when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Trail Making B test (TMB) (PG 5.5 mmol/L - PG nadir) - Change in TMB from a PG concentration of 5.5 mmol/L (100 mg/dL) until PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Measured in sec Change in performance in the TMB (a cognitive ability test) from the time point when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Hypoglycaemic symptoms score (HSS) (PG 5.5 mmol/L - PG nadir) - Change in HSS from a PG concentration of 5.5 mmol/L (100 mg/dL) to PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Test score (arbitrary units) Change in symptoms of low blood sugar from the time point when blood sugar is normal [5.5 mmol/L (100 mg/dL)] until the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Hypoglycaemia awareness (HA) (PG nadir) - HA at PGnadir after 2 and 3 times the individualised optimal basal dose of insulin | Yes/No Number of subjects with a feeling of low blood sugar at the time point when blood sugar is at a minimum level after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| AUC (GIR, recovery, PG nadir -PG 5.5 mmol/L) - Area under the glucose infusion rate-time profile during recovery from PGnadir to a PG concentration of 5.5 mmol/L (100 mg/dL) after 2 and 3 times the individualised optimal basal dose of insulin | Measured in mg/kg Amount of glucose needed to be infused to increase blood sugar from a minimum level to a normal level [5.5 mmol/L (100 mg/dL)] during recovery from low blood sugar after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| AUC (GIR, recovery, PG 5.5 mmol/L, 0-6h)-Area under the glucose infusion rate-time profile during 6 hours at a PG concentration of 5.5 mmol/L (100 mg/dL) after recovery from hypoglycaemia after 2 & 3 times the individualised optimal basal dose of insulin | Measured in mg/kg Amount of glucose needed to be infused to keep blood sugar at a normal level [5.5 mmol/L (100 mg/dL)] for 6 hours after recovery from low blood sugar after receiving a double or triple dose of basal insulin | From start of hypoglycaemia induction after 2 and 3 times the individualised optimal basal dose of insulin (day 17/day 38 for insulin 287, day 4/day 11 for insulin glargine) until termination of the clamp the following day | 
| Clinically significant hypoglycaemia (Triple dose) - Clinically significant hypoglycaemia [PG less than 3.0 mmol/L (54 mg/dL)], after 3 times the individualised optimal basal dose of insulin | Yes/No Blood sugar lower than 3.0 mmol/L (54 mg/dL) after receiving a triple dose of basal insulin Number of subjects experiencing an event is to be reported | From start of hypoglycaemia induction after 3 times the individualised optimal basal dose of insulin (day 38 for insulin 287, day 11 for insulin glargine) until termination of the clamp the following day |