Centre National de Référence sur les Microangiopathies Thrombotiques
Avancer dans la recherche pour mieux comprendre et traiter les microangiopathies thrombotiques
Research
Clinical trials completed
ADZYNMA® (TAK-755)
L'étude TAK-755-3002 est un essai de continuation phase 3b prospectif multicentrique en ouvert, promu par Takeda Development Center Americas.
Elle évalue la sécurité à long terme et l'efficacité prophylactique/à la demande de l'ADAMTS13 recombinant (rADAMTS13 = ADZYNMA®) dans le purpura thrombotique thrombocytopénique congénital (cPTT).
Rationnel
Le cTTP (Upshaw-Schulman) est une maladie héréditaire ultra-rare liée à un déficit complet ADAMTS13. Les plasmaféresis prophylactiques standards exposent à des risques infectieux, allergiques et volémiques. ADZYNMA® = 1ère thérapie enzymatique substitutive recombinante spécifique.
Objectif
L'objectif principal évalue la sécurité à long terme (incidence TEAEs/SAEs) de TAK-755 (rADAMTS13).Les objectifs secondaires mesurent efficacité prophylactique, résolution crises aiguës, immunogénicité (anticorps neutralisants) et
pharmacocinétique.
Design
Phase 3b, prospective, ouverte, multicentrique, bras unique de continuation. 77 patients cTTP sévères (~57 post-étude pivot 281102 + 20 TAK-755 naïfs). Posologie : prophylaxie 40 UI/kg/2 semaines, crise aiguë J1=40/J2=20/J3+=15 UI/kg/j.
Documents de l'étude
DARATEUMUMAB
The daratumumab study is a French multicenter observational study conducted by the CNR-MAT (Saint-Antoine Hospital, Pr Paul Coppo) , published in the British Journal of Haematology (DOI: 10.1111/bjh.19752).
It evaluates the efficacy and safety of daratumumab in 7 patients (9 episodes) with multi-resistant or rituximab-intolerant immune TTP (iTTP) .
Rational
Multidrug-resistant PTTi ( ADAMTS13 persistence <20% after rituximab + ≥2 lines) remains a major challenge despite PE, caplacizumab, and immunosuppressants. Daratumumab (anti-CD38) targets long-lived plasma cells producing anti-ADAMTS13 autoantibodies, where anti-CD20 and conventional immunosuppressants fail.
Objective
The primary objective demonstrates ADAMTS13 improvement in 8/9 episodes (including 3 normalizations), median response time 28 days, ADAMTS13 RFS 12 months 56%. Retreatment was effective in 2/3 relapses.
Design
Retrospective multicenter study CNR-MAT (Paris, Nancy, La Roche/Yon, Toulouse, Pitié-Salpêtrière) . 7 patients (4F/3M), median age 62 years, median of 3 prior lines of therapy (rituximab 100%, ciclosporin 43%, ofatumumab 29%). Indications: 8 preemptive episodes ADAMTS13 (<20%), 1 acute phase (rituximab neutropenia).
Daratumumab: IV 16 mg/kg or SC 1800 mg, median 6 infusions (2-40).
Main results
• ADAMTS13 response: 89% (≥20%), 33% normalization
• Median response time: 28 days
• RFS ADAMTS13 12 months: 56% (median not reached)
• Median TTNT: 9 months
• Safety: 56% infusion reactions (non-serious)
• Retreatment: Effective in 2/3 relapses
Study documents
RAVULIZUMAB
The RAVULIZUMAB study is a phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial sponsored by Alexion (Amgen).
It aims to evaluate the efficacy and safety of ravulizumab, a long-acting C5 inhibitor, vs placebo in adults with thrombotic microangiopathy (TMA) associated with a trigger (infection, drug, transplant, malignant hypertension, autoimmunity).
Rational
Secondary TMA occurs after further activation by various triggers (infection, medications, organ transplantation, malignant hypertension). Eculizumab has shown efficacy, but the studies were retrospective or uncontrolled. Ravulizumab, with its prolonged half-life (8 weeks vs. 2 weeks), is being prospectively evaluated for C5 inhibition in this heterogeneous population with severe acute kidney injury.
Objective
The primary objective is the proportion of patients achieving a Complete TMA Response at week 26, defined as normalization of hematological parameters + improvement in renal function. Secondary objectives include TMA response time, hematological/renal response, increase in Hb ≥2g/dL, eGFR evolution, dialysis duration, and TMA relapse.
Design
Phase 3, randomized 1:1 (ravulizumab vs placebo) + best supportive care, double-blind, stratified by initial dialysis and primary trigger type. N=100 adults (≥18 years) with TMA + trigger ≤14 days + severe acute kidney injury.
Scheme: Dose loading weight-based J1, then J15, then q8 weeks (26 weeks treatment + 26 weeks follow-up).
Key inclusion criteria
• Confirmed TMA: thrombocytopenia + microangiopathic hemolysis + LDH↑
• Trigger ≤14 days: infection/autoimmune/transplant/medication/malignant hypertension
• Severe acute renal failure
• Exclusion: Genetic atypical HUS, TTP, active N. meningitidis infection
Study documents
CAPLA 1000
L'étude CAPLA-1000 est une étude rétrospective multicentrique internationale menée par l'International Working Group on TTP (IWG-TTP) consacrée au purpura thrombotique thrombocytopénique immunologique (PTTi), s’appuyant sur le réseau des microangiopathies thrombotiques, incluant le Centre National de Référence des Microangiopathies Thrombotiques (CNR-MAT).
Elle compare 1015 patients PTT immunologique traités par caplacizumab + échanges plasmatiques + immunosuppresseurs à 510 témoins historiques, prouvant une survie 3 mois de 98,5% vs 94%.
Objectif
L'objectif principal démontre une survie 3 mois de 98,5% avec caplacizumab vs 94% témoins (OR mortalité 4,2, p<0.0001).Les objectifs secondaires valident réduction réfractarité (1% vs 10%), exacerbations (4% vs 32%), accélération réponse clinique et réduction charge PE.
Méthodologie
Cette étude repose sur la collecte standardisée de données cliniques et biologiques issues de la prise en charge des patients.Les informations recueillies incluent les caractéristiques initiales, les modalités thérapeutiques (caplacizumab en association avec les échanges plasmatiques et l’immunosuppression), ainsi que le suivi évolutif à court et moyen terme.
Critères d’évaluation
• Réponse clinique et biologique au traitement
• Délai de récupération plaquettaire
• Survenue d’exacerbations et de rechutes
• Survie
• Tolérance du caplacizumab, notamment le risque hémorragique
• Impact sur la prise en charge (recours aux échanges plasmatiques, durée d’hospitalisation)
Résultats principaux
Survie 3 mois : 98,5% vs 94% (p<0.0001)
Réponse clinique : 5j vs 6j (p<0.0001), 5 PE vs 7 PE
Réfractarité : 1% vs 10%, exacerbations : 4% vs 32%
Saignements majeurs caplacizumab : 2,4%
Documents de l'étude
CAPLAVIE
The CAPLAVIE study is a multicentre observational study conducted within the framework of the French network of thrombotic microangiopathies, including the National Reference Centre for Thrombotic Microangiopathies (CNR-MAT).
Its objective is to evaluate, under real-life conditions, the efficacy and tolerability of caplacizumab in the management of immune thrombotic thrombocytopenic purpura (ITP) . This molecule, a nanobody targeting von Willebrand factor, inhibits the interaction between ultra-large multimers of von Willebrand factor and platelets, thus limiting microthrombi formation.
The study analyzes clinical data from patients treated with caplacizumab in combination with standard therapies, including plasma exchange and immunosuppression. Evaluation criteria include the speed of platelet recovery, prevention of exacerbations, the occurrence of adverse events, and reductions in the need for plasma exchange and length of hospital stay.
The results from CAPLAVIE help to better define the place of caplacizumab in the therapeutic strategy of PTTi and to optimize its use in a personalized medicine approach.
Study documents