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1 Supplementary Online Content Lingvay I, Manghi FP, García-Hernández P, et al. Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with type 2 diabetes: the DUAL V randomized clinical trial. JAMA. doi: /jama etable 1. Sensitivity Analyses for Primary End Point and Secondary End Points etable 2. Patient-Reported Outcomes etable 3. Vital Parameters at Baseline and efigure 1. Rate of Confirmed Hypoglycemia by End of Trial HbA 1c efigure 2. Nausea Over Time ereferences This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Sensitivity Analyses for Primary End Point and Secondary End Points Treatment difference (insulin degludec/liraglutide insulin glargine) (95% CI) P-value (two-sided) Change in HbA 1c MMRM ETD 0.66% ( 0.80 to 0.52) MI PM 1 ETD 0.59% ( 0.73 to 0.45) MI PM 2 ETD 0.56% Change in body weight MMRM MI PM 1 MI PM 2 ( 0.71 to 0.42) ETD 3.31 kg ( 3.90 to 2.72) ETD 3.10 kg ( 3.70 to 2.51) ETD 2.98 kg ( 3.58 to 2.38) Treatment ratio (insulin degludec/liraglutide) (95% CI) Rate of confirmed hypoglycemia MI RE 1 ERR 0.46 ( 0.32 to 0.66) P-value (two-sided) MI RE 2 ERR 0.44 ( 0.31 to 0.63) ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference; ERR, estimated rate ratio; MI, multiple imputation; MMRM, mixed-model repeated measures; PM, pattern mixture model using sequential ANOVAs to impute values 1 ; RE, recurrent event Bayes negative binomial where events in the missing time period were imputed. 2 MMRM: Linear mixed model with visit, treatment and region as fixed factors and baseline response as covariate. Furthermore, the model includes interaction terms between visit and all other factors and the covariate. The MMRM sensitivity analysis on HbA1c was pre specified in protocol. The remaining sensitivity analyses are due to a regulatory process where FDA requested those. They are described in detail in the Appendix of submission package. MI PM 1: Patients on insulin degludec/liraglutide were assumed to have been switched to IGlar at the point of treatment discontinuation. Change in HbA 1c and body weight after 26 weeks were analyzed using an ANOVA model with treatment and region as fixed factors and baseline response as covariate. For HbA1c the non-inferiority limit of 0.3 was added to imputed values for IDegLira withdrawals. 3 MI PM 2: Patients on insulin degludec/liraglutide that discontinued treatment were assumed to have been treated with insulin glargine for the entire trial. Otherwise as MI PM 1. MI RE 1: Patients on insulin degludec/liraglutide were assumed to have been switched to insulin glargine at the point of treatment discontinuation. Number of hypoglycemic episodes during 26 weeks were analyzed using a negative binomial regression model with a log link and the logarithm of the exposure time as offset. The model includes treatment and region as fixed factors. The

3 difference in treatment effect was back transformed to event per time scale to produce a treatment rate ratio. MI RE 2: Patients on insulin degludec/liraglutide that discontinued treatment were assumed to have been treated with insulin glargine for the entire trial. Otherwise as MI RE 1.

4 etable 2. Patient-Reported Outcomes SF-36 Physical score SF-36 Physical functioning SF-36 Role-physical SF-36 Bodily pain SF-36 General health SF-36 Mental score SF-36 Vitality SF-36 Social functioning SF-36 Role-emotional SF-36 Mental health TRIM-D Total score Insulin degludec/ liraglutide 47.4 (46.4 to 48.5) 49.0 (48.0 to 50.0) 47.0 (45.8 to 48.1) 47.6 (46.5 to 48.7) 46.6 (45.4 to 47.8) 47.8 (46.8 to 48.9) 49.4 (48.1 to 50.8) 51.2 (50.0 to 52.4) 42.9 (41.9 to 44.0) 46.2 (45.2 to 47.3) 46.7 (45.4 to 48.1) 48.4 (47.2 to 49.5) 50.8 (49.6 to 52.1) 53.0 (51.9 to 54.1) 47.2 (46.0 to 48.4) 48.7 (47.6 to 49.8) 45.3 (44.0 to 46.7) 46.2 (45.0 to 47.4) 45.9 (44.5 to 47.2) 47.8 (46.5 to 49.0) 74.6 (73.1 to 76.2) 82.1 (80.6 to 83.7) Insulin glargine 47.7 (46.7 to 48.7) 47.2 (46.1 to 48.3) 47.5 (46.4 to 48.6) 46.5 (45.3 to 47.7) 47.2 (46.0 to 48.4) 46.7 (45.6 to 47.9) 50.0 (48.7 to 51.3) 49.4 (48.0 to 50.8) 43.6 (42.5 to 44.7) 45.0 (43.9 to 46.1) 48.1 (46.9 to 49.3) 49.1 (47.9 to 50.2) 51.2 (50.0 to 52.3) 52.7 (51.5 to 53.9) 48.8 (47.7 to 49.9) 49.0 (47.9 to 50.0) 46.1 (44.8 to 47.3) 45.5 (44.2 to 46.8) 47.6 (46.3 to 48.9) 48.6 (47.4 to 49.8) 73.6 (72.1 to 75.1) 78.9 (77.4 to 80.4) Estimated treatment difference (Insulin degludec/liraglutideinsulin glargine) (95% CI) P- value 1.9 (0.8 to 3.1) < (0.0 to 2.7) ( 0.0 to 2.6) (0.4 to 3.6) (0.4 to 2.9) ( 1.5 to 1.3) ( 0.8 to 1.7) ( 0.9 to 1.8) ( 0.7 to 2.6) ( 1.5 to 1.4) (0.9 to 4.7).003

5 TRIM-D Treatment burden score TRIM-D Daily life score TRIM-D Diabetes management score TRIM-D Compliance score TRIM-D Psychological health score 66.0 (63.5 to 68.6) 76.1 (73.7 to 78.5) 82.9 (80.9 to 84.9) 85.4 (83.4 to 87.5) 57.5 (55.1 to 59.8) 71.3 (68.9 to 73.6) 82.0 (79.9 to 84.1) 88.3 (86.6 to 90.1) 83.1 (81.1 to 85.0) 88.3 (86.6 to 90.0) 64.4 (62.2 to 66.6) 71.6 (69.3 to 73.9) 81.4 (79.3 to 83.4) 83.5 (81.4 to 85.5) 56.3 (53.8 to 58.8) 63.7 (61.5 to 65.9) 81.4 (79.4 to 83.4) 87.3 (85.4 to 89.1) 82.6 (80.7 to 84.6) 86.7 (84.9 to 88.5) 3.7 (0.7 to 6.8) ( 1.3 to 4.0) (4.2 to 10.2) < ( 1.2 to 3.5) ( 0.7 to 3.6).176 ANCOVA, analysis of covariance; CI, confidence interval; FAS, full analysis set; LOCF, last observation carried forward; SF-36, Short form (36) health survey; TRIM-D, Treatment Related Impact Measure for Diabetes. Observed data are mean (95% confidence intervals). Scores can range from for TRIM-D. For SF-36, raw scores can range from but data are transformed to a norm-based distribution with a mean of 50 and a standard deviation of 10. Minimal clinically important difference are available for SF-36 but are not specific to diabetes: physical score = 2; physical functioning = 3; role-physical = 3; bodily pain = 3; general health = 2; mental score = 3; vitality = 2; social functioning = 3; roleemotional = 4; mental health = 3. 4 Minimal clinically important differences are not available for TRIM-D. Treatment difference is based on a FAS (all randomized patients) and is estimated from an ANCOVA method with treatment and region as fixed factors and baseline response as covariate. Missing data are imputed using LOCF. This was a predefined statistical analyses as per the protocol. CIs are provided as descriptive statistics to meet journal style.

6 etable 3. Vital Parameters at Baseline and Parameter Insulin degludec/liraglutide (n=278) Insulin glargine (n=279) Pulse rate (bpm) 74.9 (9.4) 78.0 (9.4) 74.0 (9.3) 73.8 (10.4) Systolic blood (13.8) (12.5) (13.8) (13.3) pressure (mmhg) Diastolic blood pressure (mmhg) 79.4 (8.4) 78.7 (8.4) 78.7 (8.3) 77.4 (8.3) SD, standard deviation. Data are mean (SD) based on full analysis set (all randomized patients) for blood pressure and safety analysis set (all patients receiving at least one dose of trial product) for pulse rate. The vital parameters are descriptive statistics per protocol.

7 efigure 1. Rate of Confirmed Hypoglycemia by End of Trial HbA 1c Obs. rate, observed rate; PYE, patient-year of exposure. Data are based on the full analysis set (all randomized patients). Missing end-of-treatment HbA 1c values are imputed using last observation carried forward. Observed rates of hypoglycaemia events (dots, diamonds) are plotted by the mean value of each end-of-trial HbA1c quartile in each group. For the degludec/liraglutide group, ranges for end-of-trial HbA1c quartiles were 4.8% to 5.8%; 5.9% to 6.3%; 6.4% to 6.9%; and 7.0% to 10.3%. For the glargine group, ranges for end-of-trial HbA1c quartiles were 5.0% to 6.3%; 6.4% to 6.9%; 7.0% to 7.6%; and 7.7% to 10.8%. An observed rate is total hypoglycemic events divided by total exposure for the subjects in question. Model rates (curves) are based on a negative binomial regression model with treatment as factor, end-of-trial HbA 1c as covariate and the interaction between treatment and end-of-trial HbA 1c. The rate of hypoglycemia decreased with increasing end-of-trial HbA 1c with insulin degludec/liraglutide and patients in the insulin degludec/liraglutide group had a lower rate of hypoglycemia than patients in the insulin glargine group at all levels of glycemic control. Total treatment exposure was patient-years for insulin degludec/liraglutide and patient-years for insulin glargine.

8 efigure 2. Nausea Over Time Observed data from safety analysis set (all patients receiving at least one dose of trial product). Based on descriptive statistics per protocol.

9 ereferences. 1. O'Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for Practitioners Keene ON et. al. Missing data sensitivity analysis for recurrent event data using controlled imputation. Pharm Stat 2014;13(4): Koch GG. Comments on 'Current issues in non-inferiority trials' by Thomas R. Fleming, Statistics in Medicine, DOI: /sim Stat Med 2008;27(3): Maruish ME (Ed). User s manual for the SF-36v2 Health Survey (3rd ed). Lincoln, RI: QualityMetric Incorporated.