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1 Efficacy and safety of insulin glargine 300 U/mL vs insulin degludec 100 U/mL in insulin-naïve adults with type 2 diabetes mellitus: Design and baseline characteristics of the BRIGHT study Alice Cheng 1, Julio Rosenstock 2, Robert Ritzel 3, Zsolt Bosnyak 4, Christine Devisme 5, Xiangling Wang 6, Jochen Sieber 7, Ronan Roussel 8, Geremia B. Bolli 9 1 Division of Endocrinology and Metabolism, University of Toronto, Toronto, ON, Canada; 2 Dallas Diabetes Research Center at Medical City, Dallas, TX, USA; 3 Klinikum Schwabing and Klinikum Bogenhausen, Städtisches Klinikum München GmbH, Munich, Germany; 4 Sanofi, Paris, France; 5 AIXIAL, Boulogne-Billancourt, France; 6 Sanofi, Beijing, China; 7 Medical Affairs DCV Sanofi, Frankfurt, Germany; 8 Assistance Publique Hôpitaux de Paris, Bichat Hospital, Paris, France; 9 Perugia University Medical School, Perugia, Italy NCT Number: NCT ZINC code: SAGLB.DIA Date of preparation: March 2018

2 Disclosures of Robert Ritzel Honoraria/expenses: AstraZeneca, Boehringer Ingelheim, Berlin-Chemie, Eli Lilly, MSD, Novartis, Novo Nordisk, Sanofi Consulting/advisory boards: AstraZeneca, Novo Nordisk, Sanofi, Servier This study was sponsored by Sanofi. The authors received editorial/writing support in preparing this ATTD presentation from Arthur Holland of Fishawack Communications Ltd, funded by Sanofi

3 Introduction and rationale Gla-300 and IDeg-100 are newer BIs with improved properties and hypoglycemia risk profiles vs first-generation BI analogs 1 4 Comparisons of Gla-300 vs IDeg-100 PK/PD in T1DM Bailey et al : Gla-300 showed less fluctuating steady-state PD profiles (lower within-day variability) and more evenly distributed PK profiles vs IDeg-100 Heise et al : IDeg-100 showed lower within-day and day-to-day variability in glucose lowering effect vs Gla-300 BEGIN vs EDITION T2DM trial-level meta-analysis 7 (manuscript submitted) IDeg-100 vs Gla-100: less HbA1c improvement but nocturnal hypoglycemia benefit for IDeg-100 Gla-300 vs Gla-100: similar HbA1c reduction and hypoglycemia benefit both at night and any time of day for Gla-300 DELIVER-D (N=3746) real-world T2DM switch study (E-Poster EP10 at ATTD) Switching from Gla-100 to Gla-300 or IDeg-100 resulted in comparable improvement in glycemic control and hypoglycemia risk LIGHTNING (N=130,155) real-world T2DM study (E-Poster discussion EPD-01 at ATTD) Rates of severe hypoglycemia were similar for Gla-300 vs IDeg-100 and significantly lower vs first-generation BIs without compromising HbA1c reduction BI, basal insulin; Gla-100, insulin glargine 100 U/mL; Gla-300, insulin glargine 300 U/mL; IDeg-100, insulin degludec 100 U/mL; PD, pharmacodynamic; PK, pharmacokinetic; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus 1. Heise T, et al. Expert Opin Drug Metab Toxicol 2015;11: ; 2. Becker RH, et al. Diabetes Care 2015;38:637 43; 3. Ritzel R, et al. Diabetes Obes Metab doi: /dom [Epub ahead of print] 4. Ratner RE, et al. Diabetes Obes Metab 2013;15:175 84; 5. Bailey TS, et al. Diabetes Metab 2017 Nov 16. pii: S (17) ; 6. Heise T, et al. Diabetes Obes Metab 2017;19: Rosenstock J, et al. Diabetes 2016; 65(Supplement 1): A249

4 Introduction and rationale (continued) Available comparison data show Gla-300 and IDeg-100 appear to provide (vs first generation BI analogs): Similar glycemic control Reduced risk of hypoglycemia Currently, there are no direct head-to-head RCTs comparing the efficacy and safety of Gla-300 vs IDeg-100 Direct clinical comparisons would provide evidence to support treatment decisions OBJECTIVE To evaluate the efficacy and safety of Gla-300 compared with IDeg-100 in insulin-naïve people with T2DM who were inadequately controlled with OADs, with/without GLP-1 RAs GLP-1 RAs, glucagon-like peptide-1 receptor agonists; OADs, oral antihyperglycemic drugs; RCT, randomized controlled trial

5 Participating countries Country Investigational sites USA 73 Bulgaria 3 Croatia 3 Czech Republic 8 Denmark 4 France 6 Greece 4 Hungary 4 Israel 7 Italy 12 Romania 13 Serbia 3 Slovakia 5 Sweden 2 Switzerland 2 UK 6 Total 155

6 Insulin dose and titration Gla-300 and IDeg-100 were self-administered (QD) between 18:00 hrs and 20:00 hrs Starting daily doses (as per label): Gla-300, 0.2 U/kg; IDeg-100, 10 U Titrated weekly a to target fasting SMPG of mg/dl ( mmol/l) without hypoglycemia: Median b fasting SMPG, mg/dl (mmol/l) Gla-300 and IDeg-100 dose change >140 (>7.8) +6 U > (> ) +4 U > (> ) +2 U ( ) 0 <80 (<4.4) OR 1 symptomatic hypoglycemia episode in preceding week 2 U or at investigator s discretion Titration performed to achieve target within 8 12 weeks, post randomization a Doses titrated at least weekly, but no more than every 3 days; b From last 3 measurements QD, once daily; SMPG, self-monitored plasma glucose

7 Study design Participants Insulin-naïve adults ( 18 years) with T2DM, inadequately controlled on OADs with/without a GLP-1 RA at a stable dose for at least 3 months Screening (2 weeks) Eligible patients: 18 years T2DM duration 1 year HbA1c % at screening BMI kg/m 2 OAD use ± GLP-1 RAs at stable dose for 3 months No prior insulin use a Open-label treatment period (24 weeks) Gla-300 QD (n=462) IDeg-100 QD (n=462) Post treatment (7 days) Follow-up Follow-up Randomization 1:1 Participants stratified by HbA1c (<8.0; 8.0 %) and SU or glinide use (Yes; No) a With the exception of a maximum of 8 consecutive days or 15 days total prior insulin use BMI, body mass index; SU, sulfonylureas Treatment end Primary endpoint Study end

8 Study endpoints Primary efficacy endpoint: Change in HbA1c from baseline to week 24 Non-inferiority and then superiority of Gla-300 vs IDeg-100 was assessed Secondary efficacy endpoints: Change in FPG and fasting SMPG Variability of 4-point and 8-point SMPG profiles Percentage of participants reaching HbA1c targets (<7.0; 6.5%) Without confirmed ( 70 mg/dl or <54 mg/dl) or severe hypoglycemia Safety endpoints: Incidence and annualized rates of hypoglycemia a TEAEs Patient-reported outcomes: DTSQ, HABS a Defined according to ADA criteria 1,2 ADA, American Diabetes Association; DTSQ, Diabetes Treatment Satisfaction Questionnaire; FPG, fasting plasma glucose; HABS, Hypoglycemic Attitudes and Behavior Scale; TEAE, treatment-emergent adverse event 1. Seaquist ER, et al. Diabetes Care 2013;36: ; 2. ADA. Standards of Care in Diabetes, Diabetes Care 2017;40:S1 135

9 Participant disposition and baseline characteristics Gla-300 N=466 IDeg-100 N=463 Gla-300 (N=466) IDeg-100 (N=463) Randomized and treated: n=462 (99.1%) Completed 24-week study period: n=443 (95.1%) Discontinued: n=19 (4.1%) 4 AE (0.9%) 4 Poor compliance to protocol (0.9%) 11 Other (2.4%) Randomized and treated: n=462 (99.8%) Completed 24-week study period: n=432 (93.3%) Discontinued: n=30 (6.5%) 5 AE (1.1%) 1 Hypoglycemia (0.2%) 3 Poor compliance to protocol (0.6%) 21 Other (4.5%) Age, years 60.6 ± ± 9.8 Sex (male/female), n (%) 247/ /211 (53.0/47.0) (54.4/45.6) BMI, kg/m ± ± 4.4 Known T2DM duration, years 10.5 ± ± 6.5 Number of prior non-insulin antihyperglycemic treatments used, n (%) 0 0 (0.0) 1 (0.2) 1 70 (15.0) 65 (14.0) (38.4) 187 (40.4) >2 217 (46.6) 210 (45.4) Values are mean unless stated otherwise Randomized population. Data expressed as mean ± SD unless stated otherwise. AE, adverse event

10 Baseline characteristics (background therapy) Background therapy use was similar between the treatment groups Gla-300 (N=466) IDeg-100 (N=463) Prior non-insulin antihyperglycemic treatments, n (%) Metformin 428 (91.8) 422 (91.1) SU 301 (64.6) 309 (66.7) DPP-4 inhibitors 121 (26.0) 106 (22.9) SGLT-2 inhibitors 62 (13.3) 62 (13.4) GLP-1 RAs 46 (9.9) 65 (14.0) Thiazolidinediones 21 (4.5) 24 (5.2) Glinides 12 (2.6) 9 (1.9) Alpha-glucosidase inhibitors 9 (1.9) 7 (1.5) Other 1 (0.2) 1 (0.2) Randomized population. DPP-4, dipeptidyl peptidase 4; SGLT-2, sodium-glucose co-transporter-2

11 Proportion of participants (%) Successful titration Both groups titrated insulin effectively; overall, 47% of participants reached target HbA1c <7.0% Proportion of participants achieving HbA1c <7.0% Gla-300 (N=462) IDeg-100 (N=462) 0 Baseline Week 12 Week 24 Modified intent-to-treat population

12 Safety No specific safety concerns were reported One death occurred in the Gla-300 group Adenocarcinoma of the colon deemed unrelated to study treatment n (%) Gla-300 (N=462) IDeg-100 (N=462) Participants with any TEAE 202 (43.7) 221 (47.8) Participants with any treatment-emergent serious AE 21 (4.5) 20 (4.3) Participants with any TEAE leading to death 1 (0.2) 0 (0.0) Participants with any TEAE leading to permanent 4 (0.9) 5 (1.1) treatment discontinuation

13 Conclusions This head-to-head RCT is the first to compare the efficacy and safety of Gla-300 and IDeg-100 Participant demographics were typical of the target population a and well balanced between treatment arms ~50% of participants in both groups achieved target HbA1c indicative of effective insulin titration No specific safety concerns were reported Very few participants discontinued treatment owing to AEs a Insulin-naïve adults with uncontrolled, long-standing T2DM on OAD with/without GLP-1 RA