1198-P: The M-EASE Studies: A Modeling and Simulation Approach to Further Characterize the Efficacy of Low-Dose Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes (T1DM)
Bibliographic record
Abstract
Among the two phase 3 trials of empagliflozin (EMPA) in T1DM, one (EASE-3), demonstrated diabetic ketoacidosis risk minimization by including a lower dose (2.5 mg) than approved for use in T2DM while maintaining HbA1c benefit of -0.28%. We aimed to determine the effect of HbA1c lowering of EMPA 2.5 mg by modelling and simulation in the phase 3 trial (EASE-2) that did not investigate this dose. The effect of insulin adjustment on HbA1c was also characterized. Independent of empiric data from EASE-3 (that evaluated EMPA 2.5 mg), M-EASE-2, an empirical model, evaluated the direct effect of EMPA exposure on changes in HbA1c after simulated 26- and 52-week treatment durations in the EASE-2 study. M-EASE-2 model development was informed by EASE-2 and EASE-1 (phase 2 study, included EMPA 2.5 mg) data. M-EASE-1, a semi-mechanistic model (informed by EASE-1 and EASE-2 data), simulated changes in HbA1c after a 26-week treatment period (with/without insulin dose adjustment) driven by changes in EMPA exposure, insulin dose and mean daily glucose. Trial simulations were conducted in 239 and 500 patients per dose group in M-EASE-2/-1, respectively. The models were validated using EASE-3 trial data. In M-EASE-2, the simulated mean (median; 95% CI) HbA1c change for EMPA 2.5 mg was -0.29% (-0.29; -0.39, -0.19) at Week 26 and -0.29% (-0.29; -0.40, -0.19) at Week 52. The simulations performed were consistent with EASE-3 results. In M-EASE-1, the 26-week HbA1c change for EMPA 2.5 mg was -0.28% (-0.28; -0.40, -0.09) and -0.41% (-0.40; -0.53, -0.20) with adjusted and stable insulin therapy, respectively. The HbA1c benefit from low-dose EMPA 2.5 mg that was directly observed in a phase 3 clinical trial was confirmed using two modelling approaches from independent studies. Efficacy was sustained over 52 weeks, and the approach predicted that greater efficacy of EMPA as adjunct to insulin in T1DM can be achieved on a stable vs. variable insulin dose. Disclosure B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. N. Soleymanlou: Employee; Self; Boehringer Ingelheim Canada Ltd. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck & Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. J.S. Skyler: Advisory Panel; Self; ADOCIA, Applied Therapeutics, Dance Biopharm Holdings Inc., Orgenesis Ltd., Tolerion, Inc., Viacyte, Inc. Board Member; Self; Dexcom, Inc., Intarcia Therapeutics, Inc., Moerae Matrix, Inc. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dalcor, Dialogics, Elcelyx Therapeutics, Inc., Esperion, GeNeuro Innovation, Ideal Life, Immunomolecular Therapeutics, Intrexon, Kamada, Nestlé, Sanofi, Valeritas, Inc., Zafgen, Inc. Stock/Shareholder; Self; Dexcom, Inc., Ideal Life, Intarcia Therapeutics, Inc., Intrexon, Moerae Matrix, Inc. L.M. Laffel: Advisory Panel; Self; Lilly Diabetes, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Janssen Pharmaceuticals, Inc., UpToDate. K. Liesenfeld: Employee; Self; Boehringer Ingelheim International GmbH. D. Neubacher: Employee; Self; Boehringer Ingelheim Pharma GmbH & Co. KG. M. Riggs: Consultant; Self; Boehringer Ingelheim International GmbH. C.K. Johnston: Consultant; Self; Boehringer Ingelheim International GmbH. R.J. Eudy-Byrne: Consultant; Self; Boehringer Ingelheim International GmbH. Other Relationship; Spouse/Partner; Eli Lilly and Company, Medtronic, Tandem Diabetes Care. A. Elmokadem: None. J. George: Employee; Self; Boehringer Ingelheim International GmbH. J. Marquard: Employee; Self; Boehringer Ingelheim International GmbH. V.C. Nock: Employee; Self; Boehringer Ingelheim Pharma GmbH & Co. KG. Funding Boehringer Ingelheim; Eli Lilly and Company
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".