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clinicaltrials identifier: NCT01006291

Insulin degludec does not compromise efficacy or safety when given in a flexible once-daily dosing regimen compared to insulin glargine once daily at the same time each day in type 2 diabetes. Stephen L Atkin* , Stephen Bain, Stephen Gough, Marina Shestakova, Itamar Raz, Lawrence Blonde,

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clinicaltrials identifier: NCT01006291

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  1. Insulin degludec does not compromise efficacy or safety when given in a flexibleonce-daily dosing regimen compared to insulin glargine once daily at the same timeeach day in type 2 diabetes Stephen L Atkin*,Stephen Bain, Stephen Gough, Marina Shestakova, Itamar Raz, Lawrence Blonde, Luigi Meneghini, Kamilla Begtrup, Thue Johansen and Kåre I Birkeland *Michael White Diabetes Centre, Hull York Medical School, Hull, UK www.clinicaltrials.gov identifier: NCT01006291

  2. Background: Assessing flexibility in insulin dosing • Current basal insulin preparations should be injected at a consistent time each day to ensure optimal action • Inconvenient/difficult adhering to strict dosing schedules • Inconsistent dosing can increase variability of insulin action and compromise attainment of glycaemic targets • Trial designed to test day-to-day flexibility of ultra-long-acting insulin degludec by evaluating extreme intervals of once daily dosing (8-40 h)

  3. Insulin degludec mechanism of protraction Insulin degludec di-hexamers Injected formulation Insulin degludec multi-hexamers Soluble subcutaneousdepot Insulin degludec monomers Absorption

  4. Study design IDeg OD Flex ±OADs (n=229) Patients with type 2 diabetes (n=687) IGlar OD (according to label†) ±OADs (n=230) IDeg OD (main evening meal) ±OADs (n=228) • Inclusion criteria • Type 2 diabetes ≥6 months • Previously treated with OADs and/or basal insulin • HbA1c:OADs only 7–11%Basal insulin ± OADs 7–10% • BMI ≤40 kg/m2 • Age ≥18 years 26 weeks 0 Randomisation (open label) †IGlar dosed any time of the day but the same time each day OAD: oral antidiabetic drug

  5. Treat-to-target designComparing safety at same efficacy 2. Insulins Test and comparator groups should be treated to similar goals. Similar degrees of glycemic control (test noninferior to reference) should be achieved so that comparisons among groups in frequency and severity of hypoglycemia will be interpretable in ultimate risk-benefit assessments. U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), February 2008: http://www.fda.gov/cder/guidance/index.htm, (Draft guidance, publication in progress)

  6. Participating countries Russian Federation (9.0%) Finland (5.7%) UK (4.5%) Norway (3.6%) Hungary (6.3%) Taiwan (2.2%) Serbia & Montenegro (4.8%) Mexico (5.8%) India (17.8%) Israel (11.8%) Macedonia (10.3%) Malaysia (8.0%) Argentina (4.4%) South Africa (5.8%)

  7. Subject disposition Screened 946 Failed screening criteria 259 Randomised 687 IDeg OD Flex 229 IDeg OD 228 IGlar OD 230 Withdrawals 26 AE 2 Non-compliance 3 Ineffective drug 2 Other 19 Withdrawals 24 AE 1 Non-compliance 3 Ineffective drug 2 Other 18 Withdrawals 27 AE 2 Non-compliance 3 Ineffective drug 1 Other 21 Completers 203 Completers 204 Completers 203 AE: adverse event

  8. Baseline characteristics IDeg OD arm (fixed time) presented as EASD poster 1041 Mean (±SD) unless otherwise stated

  9. morning Dosing schedule designed to test the extreme case of once daily dosing at any time of day Mon Tue Wed Thu Fri Sat Sun 8h 8h morning morning 40h 40h 40h 24h evening evening evening evening Dosing schedule for IDeg OD Flex treatment group

  10. Titration algorithm *Mean pre-breakfast PG from the preceding 3 days

  11. Pre-trial diabetes treatment Values are n (% of total in group) Pre-trial OAD Treatment: IDeg OD Flex (n=229) IGlar OD (n=230) Metformin Glinide SU TZD

  12. Results

  13. Mean HbA1c over time IDeg OD Flex (n=229) IGlar OD (n=230) Treatment difference: non-inferior 0 Mean (LOCF) ± SEM; treatment difference analysed by ANOVA adjusted by antidiabetic therapy at screening, sex, region, age and baseline HbA1c

  14. Mean FPG over time IDeg OD Flex (n=229) IGlar OD (n=230) IDeg OD Flex - IGlar OD Treatment difference: –0.42 mmol/l, p<0.05 0.0 Mean (LOCF) ± SEM; Treatment difference analysed by ANOVA adjusted by antidiabetic therapy at screening, sex, region, age and baseline HbA1c.

  15. Weight change Treatment difference: 0.27 kg, p=NS Change in weight from baseline (kg) IDeg OD Flex (n=230) IGlar OD (n=229) 82.1 kg 81.3 kg Baseline:

  16. Hypoglycaemia classification Suspected hypoglycaemia or routine PG measurement Patient able to treat self? Yes No PG <3.1 mmol/l* No Yes Not classified as trial hypoglycaemia Confirmed hypoglycaemia Severe hypoglycaemia Minor hypoglycaemia *: With or without symptoms

  17. Confirmed nocturnal hypoglycaemia 0.4 IDeg OD Flex (n=229) IGlar OD (n=230) 0.3 23% lower risk with IDeg OD Flex than with IGlar OD (p=NS) Cumulative mean number of episodes per subject 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) A nocturnal episode is any confirmed episode with time of onset between midnight and 6am

  18. Hypoglycaemia *RR = 1.03, p=NS **RR = 0.77, p=NS n: number of patients with events; %: proportion of patients with events; rate: observed rate of hypoglycaemia in episodes/patient/year RR = Rate ratio (IDeg OD Flex/IGlar OD); rates of hypoglycaemia were analysed by a negative binomial regression model, adjusted by antidiabetic therapy at screening, sex, region, and age

  19. Conclusions Insulin degludec can be dosed flexibly once daily at any time of the day in people with type 2 diabetes Insulin degludec dosed with alternating 8 and 40 h dosing intervals reduced HbA1c as effectively and reduced FPG significantly more than insulin glargine dosed at the same time every day At alternating dose intervals of 8 and 40 h, the rate of nocturnal hypoglycaemia trended lower (-23%) for insulin degludec compared to insulin glargine whereas the overall rate of hypoglycaemia was similar

  20. Back-up

  21. Adverse events None of the SAEs in the IDegFlex or IGlar OD groups were considered possibly or probably related to investigational products PYE: Patient years of exposure Table shows treatment-emergent events (defined as an event that has 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)

  22. Mean daily insulin dose mean (LOCF)

  23. 9-point self-measured plasma glucose Week0 Week26 IDeg OD Flex (n=229) IGlar OD (n=230) pre-dinner 90 min after dinner bedtime Pre BF 90 min after BF pre-lunch 90 min after lunch 04:00 AM Pre BF FAS; LOCF BF: breakfast

  24. Confirmed hypoglycaemia IDeg OD Flex (n=230) IGlar OD (n=229) Cumulative mean number of episodes per 100 patients

  25. Serious adverse events by SOC SOC: system organ class

  26. AEs occurring with a frequency >5% by SOC and PT n, number of patient; %, proportion of patient; E, number of eventsR, number of events per 100 patient-years SAS; SOC, System Organ Class; PT, Preferred Term

  27. SAEs possibly/probably related to the trial product by SOC and PT n, number of patients; %, proportion of patients; E, number of eventsR, number of events per 100 patient-years SAS; SOC, System Organ Class; PT, Preferred Term

  28. Baseline characteristics Values are mean (±SD) unless otherwise stated *Calculated, not measured

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