<b>BACKGROUND: </b>Vedolizumab is a gut-selective humanized antibody that binds the α4β7 integrin. We evaluated efficacy and safety of vedolizumab in Japanese patients with moderate-to-severe Crohn's disease (CD).<b>METHODS: </b>In this Phase 3, double-blind study (NCT02038920), 157 patients were randomized to receive intravenous vedolizumab 300 mg (n = 79) or placebo (n = 78) at Weeks 0, 2, and 6 (induction phase). Patients with CD activity index (CDAI)-70 response at Week 10 were randomized to receive vedolizumab 300 mg (n = 12) or placebo (n = 12) at Week 14, then every 8 weeks until Week 54 (maintenance phase). Primary endpoints were ≥ 100-point reduction in CDAI (CDAI-100 response) at Week 10 for induction, and clinical remission (CR: CDAI ≤ 150) at Week 60 for maintenance.<b>RESULTS: </b>At Week 10, 26.6% of patients who received vedolizumab and 16.7% who received placebo achieved CDAI-100 response (odds ratio [OR] [95% confidence interval (CI)] 1.80 [0.82-3.96]; p = 0.145). At Week 60, 41.7% of vedolizumab-treated patients and 16.7% of placebo-treated patients achieved CR (OR [95% CI] 3.57 [0.53-23.95]; p = 0.178). The incidence of adverse events was similar in both treatment groups in both induction and maintenance phases. In patients without prior anti-TNFα exposure or with inadequate response to anti-TNFα, vedolizumab showed improved outcomes over placebo in the induction phase. Age might be a possible predictive factor of CR for future research.<b>CONCLUSION: </b>Vedolizumab showed a numerically greater efficacy versus placebo as induction therapy, but the difference was not statistically significant. Vedolizumab also showed a numerically greater efficacy in maintenance therapy, and was well tolerated.
BACKGROUND: Vedolizumab safety and efficacy have been established in many populations all over the world, but have never been studied in Japan. We report results from a Phase 3, randomized, double-blind, placebo-controlled study of vedolizumab in Japanese patients with active ulcerative colitis (UC).
METHODS: Patients with moderate-to-severe UC were enrolled into Cohort 1 (double-blinded) or Cohort 2 (open-label) in the induction phase. Cohort 1 was randomized 2:1 to receive 300 mg vedolizumab or placebo, while Cohort 2 received vedolizumab 300 mg only, at Weeks 0, 2, and 6. Patients from Cohorts 1 and 2 showing a clinical response to vedolizumab at Week 10 were randomized 1:1 to receive vedolizumab or placebo (double-blinded) at Week 14 and then every 8 weeks up to Week 54 as the maintenance phase. The primary endpoint was clinical response at Week 10, for the induction phase, and clinical remission at Week 60, for the maintenance phase.
RESULTS: A total of 292 patients were enrolled into the induction phase (246 in Cohort 1, 46 in Cohort 2); 83 patients achieved response to vedolizumab and were subsequently enrolled into the maintenance phase. Clinical response rates at Week 10 were 39.6% (65/164) and 32.9% (27/82) in the vedolizumab and placebo groups in Cohort 1, respectively (adjusted odds ratio [AOR] = 1.37, 95% CI 0.779-2.399; p = 0.2722). In the maintenance phase, clinical remission rate at Week 60 was significantly higher in the vedolizumab group, at 56.1% (23/41), versus 31.0% (13/42) for placebo (AOR = 2.88, 95% CI 1.168-7.108; p = 0.0210). Most adverse events were mild to moderate in intensity, and no deaths occurred during the study period.
CONCLUSIONS: Vedolizumab showed numerically greater efficacy compared with placebo as induction therapy, but the difference was not statistically significant. Vedolizumab was significantly superior to placebo as maintenance therapy in Japanese patients with UC. Vedolizumab has favourable safety and tolerability in these patients.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT02039505.
BACKGROUND & AIMS: There is an increasing need for new treatments for patients with Crohn's disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4β7, as induction therapy.
METHODS: Patients with moderately to severely active CD (CD activity index [CDAI] score, 220-400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ≥1 TNF antagonists); we determined the proportion of patients in clinical remission (CDAI, ≤150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (N = 416), which included patients naive to TNF antagonist therapy (n = 101).
RESULTS: Among patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P = .433). At week 10, a higher proportion of this population given vedolizumab was in remission (26.6%) than those given placebo (12.1%) (nominal P = .001; relative risk, 2.2; 95% confidence interval, 1.3-3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥100-point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P = .001; relative risk, 1.8; 95% confidence interval, 1.2-2.5). Adverse event results were similar among all groups.
CONCLUSIONS: Vedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10. ClinicalTrials.gov number: NCT01224171.
BACKGROUND: Gut-selettivo blocco del traffico dei linfociti da Vedolizumab può rappresentare un trattamento efficace per la colite ulcerosa.
METODI: Abbiamo condotto due studi randomizzati, in doppio cieco, controllati con placebo integrati di vedolizumab nei pazienti con malattia attiva. Nello studio della terapia di induzione, 374 pazienti (coorte 1) ricevuti Vedolizumab (alla dose di 300 mg) o placebo per via endovenosa alle settimane 0 e 2, e 521 pazienti (coorte 2) hanno ricevuto in aperto Vedolizumab alle settimane 0 e 2, con la valutazione della malattia alla settimana 6. Nello studio di terapia di mantenimento, i pazienti in entrambi coorte che ha avuto una risposta a Vedolizumab alla settimana 6 sono stati assegnati in modo casuale a continuare a ricevere Vedolizumab ogni 8 o 4 settimane per passare al placebo per un massimo di 52 settimane. Una risposta è stata definita come una riduzione del punteggio Mayo Clinic (range da 0 a 12, con punteggi più alti indicano malattia più attiva) di almeno 3 punti e una diminuzione di almeno il 30% rispetto al basale, con una diminuzione di accompagnamento nel retto sanguinamento subscore di almeno 1 punto o un sanguinamento rettale subscore assoluto di 0 o 1.
RISULTATI: I tassi di risposta alla settimana 6 erano 47,1% e il 25,5% tra i pazienti nel gruppo vedolizumab e placebo, rispettivamente (differenza con aggiustamento per fattori di stratificazione, 21,7 punti percentuali, 95% intervallo di confidenza [IC], 11,6-31,7; P < 0,001). Alla settimana 52, il 41,8% dei pazienti che hanno continuato a ricevere Vedolizumab ogni 8 settimane, e il 44,8% dei pazienti che hanno continuato a ricevere Vedolizumab ogni 4 settimane erano in remissione clinica (punteggio Mayo Clinic ≤2 e non subscore> 1), rispetto a 15,9 % dei pazienti che sono passati a placebo (differenza adjusted, 26,1 punti percentuali per vedolizumab ogni 8 settimane rispetto al placebo [95% CI, 14,9-37,2; P <0.001] e 29,1 punti percentuali per vedolizumab ogni 4 settimane rispetto al placebo [95% CI, 17,9-40,4; P <0.001]). La frequenza di eventi avversi è stata simile nei gruppi Vedolizumab e placebo.
CONCLUSIONI: Vedolizumab è stato più efficace del placebo, come terapia di induzione e di mantenimento per la colite ulcerosa. (Finanziato dal Millennium Pharmaceuticals;. GEMINI 1 numero ClinicalTrials.gov, NCT00783718).
BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown.
METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52.
RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).
CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).
BACKGROUND: Vedolizumab è un budello biologica selettivo che ha dimostrato l'efficacia nella colite ulcerosa (CU) e malattia di Crohn (MC). Abbiamo studiato la farmacocinetica, farmacodinamica, la sicurezza, la tollerabilità e l'efficacia di una nuova formulazione di Vedolizumab prodotto da un migliorato processo di fabbricazione.
METODI: pazienti UC stati randomizzati a ricevere vedolizumab (2, 6, o 10 mg / kg) o placebo nei giorni 1, 15, 29, e 85. Sicurezza, farmacocinetica, farmacodinamica, e le valutazioni di immunogenicità sono stati eseguiti in diversi momenti attraverso giorno 253. Mayo parziali punteggi e livelli di calprotectina fecale sono stati utilizzati per valutare l'efficacia.
RISULTATI: In tutto, 46 pazienti (9 con placebo, 37 Vedolizumab) hanno ricevuto almeno una dose del farmaco in studio. La concentrazione sierica Vedolizumab rifiutato monoexponentially fino concentrazioni raggiunte 1-10 mg / ml, e poi è caduto in modo non lineare. Vedolizumab massima concentrazione sierica (C (max)) e l'area sotto la curva (AUC) aumentano proporzionalmente circa in funzione della dose. Vedolizumab α massimo saturi (4) β (7) recettori sui linfociti periferici siero a tutte le concentrazioni sieriche misurabili. Vedolizumab è stato ben tollerato, senza morti e eventi avversi che portano alla sospensione. Ad ogni valutazione di giorno 29 attraverso 253 giorni, oltre il 50% dei pazienti trattati con vedolizumab erano in risposta clinica, mentre i tassi di risposta al placebo in genere compresi tra il 22% e il 33%. Trattamento Vedolizumab ridotto i livelli di calprotectina fecale rispetto al placebo.
CONCLUSIONI: Vedolizumab hanno dimostrato una farmacocinetica dose-proporzionale e α massimo saturi (4) β (7) recettori nel range di dosaggio testati. Multipla dosaggio fino a 10 mg / kg è stato ben tollerato. Nel corso del follow-up una percentuale maggiore di pazienti trattati con Vedolizumab erano in risposta clinica rispetto a quelli che sono stati assegnati al placebo.
BACKGROUND: blocco selettiva di interazioni tra leucociti e endotelio vascolare nell'intestino è una strategia promettente per il trattamento di malattie intestinali infiammatorie.
METODI: Abbiamo condotto uno studio multicentrico, in doppio cieco, placebo-controllato di prova di MLN02, un anticorpo umanizzato al integrina alpha4beta7, nei pazienti con attiva colite ulcerosa. Noi assegnati in maniera casuale 181 pazienti per ricevere 0,5 mg di MLN02 per chilogrammo di peso corporeo, 2.0 mg per chilogrammo, o uno placebo identica-che appare per via endovenosa il giorno 1 e giorno 29. I pazienti eleggibili anche ricevuto mesalamina concomitante o nessun altro trattamento per la colite. Scores colite ulcerosa clinici e le valutazioni sigmoidoscopic sono stati valutati sei settimane dopo la randomizzazione.
RISULTATI: i tassi di remissione clinica alla settimana 6 erano 33 per cento, 32 per cento, e il 14 per cento per il gruppo la ricezione 0,5 mg di MLN02 per chilogrammo, il gruppo che riceve 2,0 mg per chilogrammo, e il gruppo placebo, rispettivamente (P = 0,03). Le proporzioni corrispondenti di pazienti che è migliorato di almeno 3 punti sulla il punteggio colite ulcerosa clinico, sono state 66 per cento, 53 per cento, e il 33 per cento (P = 0,002). Twenty-otto per cento dei pazienti trattati con 0,5 mg per chilogrammo e il 12 per cento di quelli trattati con 2.0 mg per chilogrammo ha avuto una remissione endoscopicamente evidente, come rispetto al 8 per cento di quelli riceventi placebo (P = 0,007). Per la minoranza di pazienti in cui un titolo anticorpale MLN02 maggiore di 1:125 sviluppata, la saturazione incompleta del recettore alpha4beta7 sul linfociti circolanti è stato osservato e la alcun beneficio del trattamento è stato identificabili.
CONCLUSIONI: In questo studio a breve termine, MLN02 è risultato più efficace placebo per l'induzione di remissione clinica ed endoscopica in pazienti con attiva colite ulcerosa.
Vedolizumab is a gut-selective humanized antibody that binds the α4β7 integrin. We evaluated efficacy and safety of vedolizumab in Japanese patients with moderate-to-severe Crohn's disease (CD).
METHODS:
In this Phase 3, double-blind study (NCT02038920), 157 patients were randomized to receive intravenous vedolizumab 300 mg (n = 79) or placebo (n = 78) at Weeks 0, 2, and 6 (induction phase). Patients with CD activity index (CDAI)-70 response at Week 10 were randomized to receive vedolizumab 300 mg (n = 12) or placebo (n = 12) at Week 14, then every 8 weeks until Week 54 (maintenance phase). Primary endpoints were ≥ 100-point reduction in CDAI (CDAI-100 response) at Week 10 for induction, and clinical remission (CR: CDAI ≤ 150) at Week 60 for maintenance.
RESULTS:
At Week 10, 26.6% of patients who received vedolizumab and 16.7% who received placebo achieved CDAI-100 response (odds ratio [OR] [95% confidence interval (CI)] 1.80 [0.82-3.96]; p = 0.145). At Week 60, 41.7% of vedolizumab-treated patients and 16.7% of placebo-treated patients achieved CR (OR [95% CI] 3.57 [0.53-23.95]; p = 0.178). The incidence of adverse events was similar in both treatment groups in both induction and maintenance phases. In patients without prior anti-TNFα exposure or with inadequate response to anti-TNFα, vedolizumab showed improved outcomes over placebo in the induction phase. Age might be a possible predictive factor of CR for future research.
CONCLUSION:
Vedolizumab showed a numerically greater efficacy versus placebo as induction therapy, but the difference was not statistically significant. Vedolizumab also showed a numerically greater efficacy in maintenance therapy, and was well tolerated.
