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)
Notice bibliographique
Résumé
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
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».