S305: PHASE 2 RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, MULTICENTER STUDY OF RECOMBINANT ADAMTS13 IN PATIENTS WITH IMMUNE-MEDIATED THROMBOTIC THROMBOCYTOPENIC PURPURA
Notice bibliographique
Résumé
Topic: 32. Platelet disorders Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disorder caused by a severe ADAMTS13 deficiency, due to anti-ADAMTS13 autoantibodies. iTTP treatment includes plasma exchange (PEX) and immunosuppressive therapy. A recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) is under investigation as a therapeutic option for patients with iTTP. Aims: To assess the pharmacokinetic (PK) characteristics of ADAMTS13 in patients with iTTP receiving treatment for an acute TTP episode, the PK/pharmacodynamic (PD) relationship between ADAMTS13 activity levels and biomarkers, and safety. Methods: This phase 2, randomized, placebo-controlled, double-blind, multicenter study (NCT03922308) enrolled patients aged 18–75 years experiencing an acute TTP episode. Patients received up to 1 pre-study PEX. Eligible patients were randomized 1:1:1 into three treatment arms, all with daily PEX and immunosuppressants. Arm 1: placebo given post-PEX and 12 hours post-PEX; Arm 2: rADAMTS13 40 IU/kg intravenous (IV) given post-PEX and placebo 12 hours post-PEX; Arm 3: rADAMTS13 40 IU/kg IV given post-PEX and 12 hours post-PEX. Patients received treatment until clinical remission (platelet normalization [≥150 ×109/L] and lactate dehydrogenase levels <2 × upper limit of normal for ≥48 hours following initial platelet normalization). Post-remission follow-up was 3 months and included ADAMTS13 activity-driven supplementation with placebo or rADAMTS13. Primary endpoints included ADAMTS13 activity levels and PK/PD relationships. Secondary endpoints included incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs, and changes in antibody levels. Results: Twenty-eight patients were enrolled (68% female; median [range] age, 48.5 [24–73] years): Arm 1, n=10; Arm 2, n=9; Arm 3, n=9. At baseline, mean (SD) platelet count ×109/L was 35.8 (32.1), 27.7 (17.6) and 15.4 (7.5) in Arm 1 (n=10), Arm 2 (n=9) and Arm 3 (n=8), respectively. Mean (SD) neutralizing antibody (NAb) levels BU/ml at baseline were 1.6 (1.0), 1.3 (0.3) and 2.0 (1.1) in Arm 1 (n=10), Arm 2 (n=9) and Arm 3 (n=9), respectively. Figure shows pre-remission ADAMTS13 activity time profiles. Higher plasma ADAMTS13 activity exposures were achieved in Arm 2 vs Arm 1 (up to 11.7-fold higher geometric mean [GM] for maximum concentration [Cmax] and 7.7-fold higher for area under the concentration-time curve from time zero [pre-PEX] to 0.5–3 hours after second infusion [AUC(overall)]), and Arm 3 vs Arm 1 (up to 5.4-fold and 5.8-fold higher GM for Cmax and AUC(overall) respectively). Patients positive vs negative for anti-rADAMTS13 antibodies had lower ADAMTS13 GM Cmax and AUC(overall) across all three arms. Post-remission, rADAMTS13 improved platelet counts regardless of NAb levels. While ADAMTS13 activity tracked with platelet recovery, relationship precision was low. Overall, 135 TEAEs in 10 patients and 6 serious TEAEs in 4 patients were reported in Arm 1, 67 TEAEs in 9 patients and 2 serious TEAEs in 1 patient in Arm 2, and 28 TEAEs in 8 patients and 3 serious TEAEs in 3 patients in Arm 3. No serious TEAEs were related to bleeding events or rADAMTS13. No TEAEs led to study discontinuation or death. Summary/Conclusion: rADAMTS13 plus PEX showed favorable tolerability and increased ADAMTS13 exposures compared with placebo plus PEX, leading to increasing ADAMTS13 activity levels over time in patients with iTTP. Post-remission, rADAMTS13 alone improved platelet levels. The data support a therapeutic effect of rADAMTS13 in patients with iTTP and further investigation is warranted.Keywords: ADAMTS13, Pharmacokinetic, Clinical trial, Thrombotic thrombocytopenic purpura (TTP)
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 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,003 | 0,002 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,010 | 0,002 |
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 ».