INTERVENTION: Product Name: VEDOLIZUMAB Product Code: MLN0002 Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: VEDOLIZUMAB CAS Number: 943609‐66‐3 Current Sponsor code: MLN0002 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300mg‐ Pharmaceutical form of the placebo: Solution for infusion Route of administration of the placebo: Intravenous use CONDITION: Moderate to Severe Ulcerative Colitis ; MedDRA version: 9.1 Level: LLT Classification code 10045365 Term: Ulcerative colitis PRIMARY OUTCOME: Main Objective: Primary Objective for the Induction Phase ; ; • To determine the effect of MLN0002 induction treatment on clinical response at 6 weeks; ; Primary Objective for the Maintenance Phase ; ; • To determine the effect of MLN0002 maintenance treatment on clinical remission at 52 weeks; ; ; ; ; ; Primary end point(s): Primary Endpoint for the Induction Phase:; ; • Proportion of patients with clinical response at Week 6; ; ; Primary Endpoint for the Maintenance Phase:; ; • Proportion of patients in clinical remission at Week 52; ; ; ; ; ; Secondary Objective: Secondary Objectives for the Induction Phase; ; • To determine the effect of MLN0002 induction treatment on clinical remission at 6 weeks; ; • To determine the effect of MLN0002 induction treatment on mucosal healing at 6 weeks; ; ; Secondary Objectives for the Maintenance Phase; ; • To determine the effect of MLN0002 maintenance treatment on durability of clinical response ; ; • To determine the effect of MLN0002 maintenance treatment on mucosal healing at 52 weeks; ; • To determine the effect of MLN0002 maintenance treatment on durability of clinical remission ; ; • To determine the effect of MLN0002 maintenance treatment on corticosteroid‐free remission at 52 weeks; ; ; ; ; ; INCLUSION CRITERIA: 1. Age 18 to 80 2. Male or female patient who is voluntarily able to give informed consent 3. Female patients must: • be post‐menopausal for at least 1 year before the screening visit, OR • be surgically sterile, OR • (if they are of childbearing potential) agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 6 months after the last dose of study drug, OR • agree to completely abstain from heterosexual contact. Male patients, even if surgically sterilized (ie, status post‐vasectomy), must: • agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, OR • agree to completely abstain from heterosexual contact. 4. Diagnosis of ulcerative colitis established at least 6 months prior to enrollment by clinical and endoscopic evidence and corroborated by a his
The primary purpose of this study was to determine the effect of vedolizumab induction treatment on clinical response at 6 weeks and to determine the effect of vedolizumab maintenance treatment on clinical remission at 52 weeks.
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: Vedolizumab è un umanizzato immunoglobulina G1 anticorpo monoclonale che ha come bersaglio esclusivamente il linfocita integrina [alpha] 4 [beta] 7. Questa interazione impedisce il legame di gut-homing linfociti T di mucosa di adesione delle cellule vascolari addressin molecola-1 (MAdCAM-1), riducendo in tal modo l'infiammazione gastrointestinale. Vedolizumab è attualmente in sviluppo per il trattamento della colite ulcerosa (CU) e malattia di Crohn (MC). Vedolizumab farmacocinetica (PK) i dati di fase 3 studi (GEMINI 1 e 2) profili farmacocinetici simili sono stati precedentemente pubblicati e mostrare in UC e CD populations.1,2 paziente Qui l'/ farmacodinamica (PD) rapporto PK e l'immunogenicità del vedolizumab nel GEMINI 1 e 2 studi sono descritti. METODI: La GEMINI 1 e 2 studi hanno incluso una fase di induzione di 6 settimane, durante il quale i pazienti hanno ricevuto Vedolizumab 300 mg o placebo per via endovenosa alle settimane 0 e 2 e sono stati valutati a 6 settimane. Pazienti Vedolizumab trattati che hanno avuto una risposta clinica alla settimana 6 sono stati assegnati in modo casuale a ricevere 300 mg vedolizumab (vedolizumab intention-to-treat [ITT] popolazione) o placebo (placebo popolazione ITT) ogni 4 settimane (Q4W) o ogni 8 settimane ( Q8W) durante la successiva fase di mantenimento di 46 settimane. Non responder ad induzione Vedolizumab (non-ITT popolazione) hanno ricevuto in aperto vedolizumab Q4W, ed i pazienti randomizzati a placebo durante la fase di induzione continuato a ricevere placebo fino alla settimana 52. I campioni di sangue per la determinazione delle concentrazioni Vedolizumab, valutazione PD ([alpha] 4 [beta] 7 [recettore] saturazione tramite MAdCAM-1-Fc vincolanti test di interferenza), e la valutazione di anticorpi anti-Vedolizumab sono stati raccolti in momenti pre-specificati. Le statistiche descrittive sono stati usati per riassumere Vedolizumab PK e dati di immunogenicità. Appezzamenti di saturazione dei recettori sono stati generati. RISULTATI: La somministrazione di 300 mg vedolizumab Q4W o Q8W provocato concentrazioni sieriche medie,> = 10 [micro] g / ml a tutti i tempi in entrambe le pazienti UC e CD (ITT e non ITT). In un'analisi aggregata di UC e CD pazienti (ITT e non ITT), la saturazione dei recettori completo è stato osservato alla settimana 6 e mantenuta fino alla settimana 52 sia nel Q8W vedolizumab e gruppi Q4W. Nel complesso, il 4% (56/1434) dei pazienti risultati positivi per gli anticorpi anti-vedolizumab in qualsiasi momento durante il trattamento vedolizumab. Frequenza di sviluppo di anticorpi anti-Vedolizumab off droga (settimana 66) era ~ 10% (32/320) nel pool UC e CD pazienti (ITT e non ITT). Tra i pazienti che hanno avuto una reazione correlata investigatore-definito, 5% (3/61) testato persistentemente (a> = 2 visite consecutive) positivi per gli anticorpi anti-vedolizumab. Rispetto alla popolazione generale di studio, i pazienti che sono risultati costantemente positivi per gli anticorpi anti-vedolizumab avevano generalmente concentrazioni sieriche vedolizumab valle più basse. Nel gruppo placebo ITT, l'uso di immunomodulatori concomitanti è stato associato ad un più basso tasso di anti-vedolizumab positività anticorpale (3%, 1/32) che visto senza uso di immunomodulatori concomitanti (18%, 44/247). CONCLUSIONI: Conclusioni Durante la somministrazione di vedolizumab sia Q8W o Q4W in pazienti con UC e CD, le concentrazioni sieriche vedolizumab sono stati mantenuti a> = 10 [micro] g / ml, un livello che ha provocato la saturazione dei recettori completo.
Background: Vedolizumab (VDZ), a gut-selective, humanized, anti-α4β7 integrin monoclonal antibody, was evaluated for the treatment of ulcerative colitis (UC) in the 52-week GEMINI 1 trial. In this study, 47.1% of patients had a clinical response to VDZ induction therapy at week 6. Here the efficacy of continuing VDZ therapy is evaluated in week 6 nonresponders to VDZ induction therapy. Methods: GEMINI 1 participants were randomly assigned to receive placebo (PBO) or VDZ 300 mg (cohort 1) or assigned to receive open-label VDZ (cohort 2) intravenously at weeks 0 and 2. Patients who did not respond to VDZ induction therapy at week 6 received open-label VDZ every 4 weeks (Q4W) during maintenance, whereas all PBO patients continued on PBO. Clinical response (reduction in partial Mayo Clinic score [MCS] of ≥2 points and decrease of ≥25% from the baseline score, with an accompanying reduction in rectal bleeding subscore of ≥1 point or a rectal bleeding subscore of 0 or 1) and clinical remission (partial MCS of ≤2 points and no subscore >1 point) were assessed in week 6 nonresponders at weeks 10 and 14 (prespecified) and at week 52 (post hoc). Week 52 post hoc analyses were also performed for mucosal healing (Mayo Clinic scale endoscopic subscore of 0 or 1) in week 6 nonresponders and for efficacy end points in week 6 nonresponders who had clinical response at week 10 or 14. Results: At baseline, the median duration of UC in VDZ week 6 nonresponders (4.6 years) was comparable to week 6 responders. Baseline UC activity (ie, complete MCS) was higher in VDZ week 6 nonresponders (median, 9.0) than in week 6 responders (median, 8.0), which was attributable mainly to a greater proportion of patients with MCS of 9 to 12 (56% of week 6 nonresponders, 42% of week 6 responders). Rate of previous tumor necrosis factor antagonist failure was higher among week 6 nonresponders (51%) than among week 6 responders (32%). Proportions of week 6 nonresponders who had clinical response, clinical remission, or mucosal healing at weeks 10, 14, and 52 were numerically greater with VDZ than with PBO (Table). These differences were most pronounced at week 52. For both VDZ and PBO, the proportions of week 6 nonresponders who had clinical response, clinical remission, or mucosal healing at week 52 were similar between those who responded at week 10 and those who responded at week 14; the small numbers of PBO-treated patients in these subgroups are a limitation of this analysis. Conclusions: Patients with UC who did not have a clinical response to VDZ induction therapy at week 6 and continued VDZ Q4W had higher rates of clinical response and remission at weeks 10, 14, and 52 and of mucosal healing at week 52 than did those who received PBO.
Vedolizumab (VDZ) is a selective antibody against α4β7‐integrin, which targets leukocyte trafficking in the gastrointestinal tract. The GEMINI studies are Phase 3, randomized, placebo‐controlled trials to assess the efficacy of VDZ in induction and maintenance of moderately to severely active ulcerative colitis (GEMINI 1) and Crohn's disease (GEMINI 2). Included in these studies are patients who have failed TNF‐α antagonist therapy. GEMINI 1 showed that VDZ is an effective agent in induction and maintenance of ulcerative colitis. GEMINI 2 met one of two primary end points in the induction phase showing that VDZ is more likely to induce clinical remission compared with placebo. VDZ is an effective agent in the maintenance of Crohn's disease. These studies pave the way to a new class of medications for treatment of inflammatory bowel disease.
BACKGROUND: A relationship between the pharmacokinetics (PK) of tumor necrosis factor antagonists and mucosal healing in patients with ulcerative colitis (UC) or (Figure presented) Crohn's disease was recently reported.1,2 This analysis examines the relationship between the PK of vedolizumab (VDZ), an a4β7 integrin antagonist, and endoscopic outcomes in patients with UC using population PK analysis. METHODS: In GEMINI 1 (phase 3, randomized study), patients with UC received double-blind VDZ 300 mg or placebo (cohort 1) or open-label VDZ 300 mg (cohort 2) at weeks 0 and 2 during induction.3 Week 6 VDZ responders were rerandomized to placebo or VDZ 300 mg every 4 or 8 weeks during maintenance (up to week 52); induction placebo patients and week 6 nonresponders continued on placebo and VDZ 300 mg every 4 weeks, respectively. Endoscopic evaluation was performed at weeks 0, 6, and 52; blood samples for PK evaluation were collected at various time points. First, for all VDZ-treated patients (cohorts 1 and 2) with a week 6 Mayo Clinic endoscopic subscore, median week 6 VDZ trough concentrations were determined among patients with each endoscopic subscore (range, 0-3; higher scores indicate more active disease). Then, week 6 VDZ trough concentration quartiles and associated rates of mucosal healing (endoscopic subscore ≤1) were calculated. Finally, a population PK model4 was used to estimate individual VDZ clearance values for all VDZ-treated patients with a week 6 endoscopic subscore. RESULTS: At week 6, mucosal healing was more common among patients with higher measured VDZ trough concentrations (Table 1). Week 6 median measured VDZ trough concentrations were 34.5 μg/mL for patients with an endoscopic subscore of 0 (n = 55), 30.4 μg/mL for those with a subscore of 1 (n = 223), 24.0 μg/mL for those with a subscore of 2 (n = 224), and 19.6 μg/mL for those with a subscore of 3 (n = 188) (subscores unavailable for 3 patients). Median week 6 measured VDZ trough concentrations for patients with the highest endoscopic subscores were below the overall week 6 median for GEMINI 1 (25.6 μg/mL). A trend toward higher individual estimated VDZ clearance values in patients with higher endoscopic subscores was noted (Figure 1), suggestive of faster VDZ elimination in these patients. (Figure presented) CONCLUSIONS: At week 6, endoscopic subscores were lower and mucosal healing was more common in patients with UC who had higher measured VDZ trough concentrations. The apparent association between higher endoscopic subscores and faster VDZ clearance could be attributable to several confounding factors and warrants further investigation. Additional analyses of the relationship between VDZ PK and endoscopic outcomes at week 52 of GEMINI 1 are ongoing.
Introduction: Corticosteroids (CS) are effective for the short‐term treatment of patients with ulcerative colitis (UC), but serious side effects prohibit long‐term use. In the GEMINI 1 study, a significantly higher percentage of patients with moderately to severely active UC were in CS‐free remission at week 52 with vedolizumab (VDZ) treatment than with placebo (PBO).1 Methods: In GEMINI 1, patients who responded to VDZ induction therapy at week 6 were re‐randomized to PBO or VDZ for 46 weeks. From week 6 onward, patients with clinical response to VDZ began a CS tapering regimen. We characterized CS dose reductions achieved with VDZ therapy in exploratory and post hoc analyses of patients with baseline (week 0) CS use (<30 mg/day prednisone or equivalent). Median CS dose over time, change from baseline CS dose, and CS‐free status at week 52 were summarized overall and by tumor necrosis factor antagonist (anti‐TNF) treatment (naive or failure) history. Results: Among patients with baseline CS use, 74% decreased their CS dose with VDZ treatment compared with 57% with PBO (Table). At week 52, 56% of VDZ‐treated patients compared with 32% of PBO‐treated patients were on <7.5 mg/day of CS (Table); the median CS dose was 2.5 mg/day for VDZ‐treated patients and 10.0 mg/day for PBO‐treated patients. Numerically higher percentages of VDZ‐treated patients were CS‐free for 90 or 180 consecutive days at week 52 than PBO‐treated patients (Table). Similar trends were observed in the anti‐TNF‐naive and anti‐TNF‐failure populations (Table). Conclusion: Numerically greater reductions in CS use were achieved with VDZ maintenance therapy compared with PBO. At week 52, VDZ therapy was associated with numerically higher percentages of CS‐free patients and patients who were CS‐free for 90 or 180 consecutive days than PBO. Interpretation of these post hoc analyses, including the degree of dose reduction, is limited by differing initiation weeks for CS tapering per patient and small sample sizes.. (Table Presented).
Introduction Corticosteroids (CS) are effective for the shortterm treatment of patients (pts) with ulcerative colitis (UC), but serious side effects prohibit long-term use. In the GEMINI 1 study, a higher percentage of pts with moderately to severely active UC were in CS-free remission at week (wk) 52 with vedolizumab (VDZ) treatment than with placebo (PBO).1 Methods In GEMINI 1, pts who responded to VDZ induction therapy at wk 6 were re-randomised to PBO or VDZ for 46 wks. From wk 6 onward, pts with clinical response discontinued CS use. We characterised CS dose reductions achieved with VDZ therapy in exploratory and post hoc analyses of pts with baseline (wk 0) CS use (≤30 mg/day prednisone or equivalent). Median CS dose over time, change from baseline CS dose, and CS-free status at wk 52 were summarised overall and by anti-tumour necrosis factor (anti-TNF) treatment (naïve or failure) history. Results Of pts with baseline CS use, 74% decreased their CS dose with VDZ treatment at week 52 (vs 57% with PBO) (Table). At wk 52, 56% of VDZ-treated pts were on ≤7.5 mg/ day of CS (Table), and the median CS dose was 2.5 mg/day for VDZ-treated pts and 10.0 mg/day for PBO. Numerically higher percentages of VDZ-treated pts were CS-free for 90 and 180 consecutive days at wk 52 than PBO- treated pts. Similar trends were observed in the anti-TNF-naïve and anti- TNF-failure populations. [TABLE PRESENTED] Conclusion Numerically greater reductions in CS use were achieved with VDZ maintenance therapy compared with PBO. At week 52, VDZ therapy was associated with numerically higher percentages of CS-free patients and patients who were CS-free for 90 or 180 consecutive days than PBO. Interpretation of these post hoc analyses, including the degree of dose reduction, is limited by differing initiation weeks for CS tapering per patient and small sample sizes.
Introduction In GEMINI 1 and GEMINI 2, vedolizumab (VDZ) was safe and effective in patients (pts) with ulcerative colitis (UC) or Crohn's disease (CD), respectively, on stable doses of immunosuppressants (IS).1,2 The effect of discontinuing IS in pts who responded to VDZ induction therapy in these studies has not been characterised. Methods Pts who responded to VDZ at week (wk) 6 were rerandomised to placebo (VDZ/PBO) or VDZ every 4 or 8 wks (VDZ/VDZ Q4W or Q8W) for 46 wks. At United States (US) sites, re-randomised pts discontinued IS use at wk 6. At non- US sites, pts could continue IS use. Efficacy, VDZ serum concentration, and immunogenicity data (via an enzyme-linked immunosorbent assay) were evaluated post hoc in pts with baseline IS use stratified by region. Results At wk 52, rates of clinical remission and response (Table), mucosal healing (UC), durable clinical remission, and corticosteroid-free remission were numerically higher with VDZ, mostly irrespective of IS use. The US and non-US sites had similar numbers of patients who were positive for anti- VDZ antibodies during VD maintenance therapy (Table). Mean trough concentrations were similar between US and non- US pts at wk 46. [TABLE PRESENTED] Conclusion Discontinuing IS did not appear to substantially affect efficacy of VDZ maintenance therapy. Interpretation of these post hoc analyses is limited by potential IS discontinuation in non-US pts and the relatively small sample sizes.
BACKGROUND: Health‐related quality of life (HRQL) is often diminished in patients with ulcerative colitis. AIM: To evaluate the effects of vedolizumab on HRQL in patients with ulcerative colitis. METHODS: Using maintenance phase data from the GEMINI 1 study, an analysis of covariance model was used to calculate mean differences between the vedolizumab and placebo groups in changes from baseline to week 52 for 3 HRQL instruments: The Inflammatory Bowel Disease Questionnaire (IBDQ), 36‐Item Short Form Health Survey (SF‐36), and EQ‐5D. Proportions of patients meeting minimal clinically important difference (MCID) thresholds for changes on these instruments were compared between treatment groups for the overall population and for clinically important subgroups. Concordance between clinical remission and remission defined using IBDQ scores was examined. RESULTS: Compared with placebo‐treated patients, vedolizumab‐treated patients had greater improvements (152‐201%) in IBDQ, EQ‐5D visual analogue scale (VAS), and EQ‐5D utility scores. Greater proportions (6.9‐19.9%) of vedolizumab‐treated patients than placebo‐treated patients met MCID thresholds for all the instruments. Vedolizumab‐treated patients with lower baseline disease activity and those without prior tumour necrosis factor (TNF) antagonist failure had greater HRQL improvements. Among 127 patients with clinical remission based on complete Mayo Clinic scores, >80% also had IBDQ remission; >70% of the 150 patients with IBDQ remission demonstrated clinical remission. CONCLUSIONS: Vedolizumab therapy was associated with significant improvements in HRQL measures compared with placebo. Benefits were greater in patients with lower disease activity and no prior TNF antagonist failure.
INTRODUCTION: The efficacy and safety of vedolizumab, a gut‐selective α4β7 integrin antibody, were demonstrated in the GEMINI 1 and GEMINI 2 clinical trials of adults aged 18‐80 years. We investigated the efficacy and safety of vedolizumab in patients stratified by age from the GEMINI trials. METHODS: Safety and efficacy, including clinical response, clinical remission, and corticosteroid‐free remission, at week 6 and/or 52 were determined post hoc in patients aged <35, 35 to <55, and ≥55 years. RESULTS: At baseline, 353, 412, and 130 ulcerative colitis (UC) and 582, 443, and 90 Crohn's disease (CD) patients were aged <35, 35 to <55, and ≥55. Of these patients, 56 were aged ≥65 years (UC: 33, CD: 23). Trends favoring vedolizumab over placebo were observed for most efficacy endpoints irrespective of patient age; some variability between subgroups was observed. Safety profiles of vedolizumab and placebo were similar in all age groups. Vedolizumab‐treated patients aged ≥55 had the lowest incidence of serious infections (0.9 per 100 person‐years) and adverse events leading to hospitalization (14.8 per 100 person‐years). There were no age‐related differences in the incidence of adverse hematological events, malignancy, or death. CONCLUSIONS: The safety and efficacy of vedolizumab in patients with UC or CD were similar for all age groups. The number of patients in the oldest age group in these analyses was small; thus further studies of vedolizumab in larger cohorts of elderly patients are warranted. FUNDING: Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.).
BACKGROUND & AIMS: The efficacy and safety of vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against the integrin α4β7, were demonstrated in multicenter, phase 3, randomized, placebo-controlled trials in patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease. We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC, based on past exposure to anti-tumor necrosis factor-α (TNF) antagonists.
METHODS: We performed a post hoc analysis of data from the GEMINI 1 study, collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist (naive to TNF antagonists) and 367 patients with an inadequate response, loss of response, or intolerance to TNF antagonists (failure of TNF antagonists). Predefined outcomes of GEMINI 1 were evaluated in these subpopulations.
RESULTS: At Week 6, there were greater absolute differences in efficacy between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists, although the risk ratios (RRs) for efficacy were similar for each group. Week 6 rates of response to vedolizumab and placebo were 53.1% and 26.3%, respectively, among patients naive to TNF antagonists (absolute difference, 26.4%; 95% confidence interval [CI], 12.4-40.4; RR, 2.0; 95% CI, 1.3-3.0); these rates were 39.0% and 20.6%, respectively, in patients with failure of TNF antagonists (absolute difference, 18.1%; 95% CI, 2.8-33.5; RR, 1.9; 95% CI, 1.1-3.2). During maintenance therapy, the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists, for most outcomes. Week 52 rates of remission with vedolizumab and placebo were 46.9% and 19.0%, respectively, in patients naive to TNF antagonists (absolute difference, 28.0%; 95% CI, 14.9-41.1; RR, 2.5; 95% CI, 1.5-4.0) and 36.1% and 5.3%, respectively, in patients with failure of TNF antagonists (absolute difference, 29.5%; 95% CI, 12.8-46.1; RR, 6.6; 95% CI, 1.7-26.5). No differences in adverse events were observed among groups.
CONCLUSIONS: Vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure. There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure. ClinicalTrials.gov no: NCT00783718.
Background: Vedolizumab (VDZ) achieves long term clinical remission and mucosal healing in patients (pts) with moderately‐to‐severely active ulcerative colitis (UC). Relief of rectal bleeding (RB) and stool frequency (SF) remain important treatment goals for pts and key indicators of remission for physicians. We aimed to characterize early symptomatic response with VDZ, specifcally evaluating the timing of RB and SF improvement. METHODS: We assessed symptomatic improvement with VDZ through post‐hoc analysis of GEMINI 1 data. Pts with active, moderate‐to‐severe UC were randomized to receive double‐blind placebo (PBO) or VDZ at weeks (wks) 0 and 2 during the 6‐wk induction phase. Mayo clinic SF subscores (SFS) and RB subscore (RBS) were evaluated at 0, 2, 4, and 6 wks. Mean subscores and mean percent change from baseline (BL) were reported for the overall population and in those who were tumor necrosis factor antagonist (anti‐TNF) naïve. Te percentages of pts who reached SFS=1 and/or RBS=0 were also determined. RESULTS: In anti‐TNF‐naïve pts, greater percentage decreases in mean SFS from BL were observed with VDZ vs PBO, reaching statistical signifcance at wks 4 and 6 as suggested by the non‐overlapping 95% confdence intervals. Percent change from baseline (95%CI) at wks 2, 4, and 6 were‐19.9(‐28.0,‐11.8),‐35.7(‐45.2,‐26.2) and‐36.5(‐45.0,‐28.0) respectively for VDZ and‐5.0(‐15.7, 5.7),‐0.4(‐12.8, 11.9) and‐12(‐23.4,‐0.6) respectively for PBO. Te same trends were observed in the overall population without reaching statistical signifcance. Percent change from baseline (95%CI) at wks 2, 4, and 6 were‐12.3(‐18.6,‐6.0),‐23.5(‐31.2,‐15.7) and‐25.0(‐31.6,‐18.3) respectively for VDZ and‐6.4(‐14.2, 1.5),‐9.9(‐19.5,‐0.3), and‐12.4(‐20.8,‐4.0) respectively for PBO. Similarly, a numerically greater percentage decrease from BL in RBS was observed with VDZ vs PBO, reaching statistical signifcance at wk 6 in both anti‐TNF‐naïve and overall populations. Percent change from baseline (95%CI) at wks 2, 4, and 6 for anti‐TNF‐naïve pts were‐29.8(‐39.2,‐20.4),‐45.6(‐55.4,‐35.9) and‐59.0(‐67.6,‐50.3) respectively for VDZ, and‐19.8 (‐32.3,‐7.3),‐28.0(‐40.8,‐15.3) and‐27.1(‐38.7,‐15.4) respectively for PBO. Percent change from baseline (95%CI) at wks 2, 4, and 6 for overall pts were‐28.6 (‐35.5,‐21.6),‐42.3(‐49.5,‐35.1) and‐49.5 (‐57.0,‐41.9) respectively for VDZ and‐20.7 (‐29.4,‐12.1),‐29.6(‐38.4,‐20.7) and‐26.8 (‐36.3,‐17.3) respectively for PBO. Signifcantly higher percentages of pts achieved SFS=1 or RBS=0 with VDZ vs PBO at wk 6 (32% higher with 95%CI:19.5‐44.6 and 22.9% higher with 95%CI:9.8‐36.0, respectively) and as early as wk 2 (22.2% higher with 95%CI of 9.6‐34.9 and 12.3% higher with 95%CI:0.6‐24.1, respectively) among the anti‐TNF‐naïve population. A composite of SFS=1 and RBS=0 was achieved in a signifcantly greater percentage of pts with VDZ than PBO at all time points for both anti‐TNF naïve and overall populations with treatment differences of 15.7% and 9.0% at Week 2. CONCLUSION(S): Symptomatic improvements were achieved with VDZ as early as wk 2, with greater differences from PBO observed in anti‐TNF‐naïve pts. Tese results highlight the rapid onset of VDZ in UC; however, assessing efcacy at wk 14 and beyond for those who exhibit a more gradual response should be used to inform clinical practice.
ABSTRACT
Background and Aims
Vedolizumab, a humanised monoclonal antibody for the treatment of inflammatory bowel disease, selectively blocks gut lymphocyte trafficking. This may reduce the risk of respiratory tract infections [RTIs] compared with systemic immunosuppressive therapies. To assess this possibility, we evaluated the rates of RTIs in clinical trials of vedolizumab.
METHODS
Patient-level data from Phase 3 randomised controlled trials [RCTs] of vedolizumab in ulcerative colitis [UC; GEMINI 1] and Crohn’s disease [CD; GEMINI 2], and a long-term safety study [UC and CD] were pooled. Cox proportional hazards models were used to estimate the incidence of upper RTIs [URTIs] and lower RTIs [LRTIs] with adjustment for significant covariates.
RESULTS
In the RCTs [n = 1731 patients], the incidence of URTIs was numerically higher in patients receiving vedolizumab compared with those receiving placebo, although this difference was not statistically significant (38.7 vs 33.0 patients per 100 patient-years; hazard ratio [HR] 1.12; 95% confidence interval [CI]: 0.83–1.51; p = 0.463). The rate of LRTIs, including pneumonia, was numerically lower in the vedolizumab versus the placebo group: this difference was not statistically significant (7.7 vs 8.5 per 100 patient-years [HR 0.85; 95% CI: 0.48–1.52; p = 0.585]). Both URTIs and LRTIs were more frequent in patients with CD compared with UC. Most RTIs in patients receiving vedolizumab were not serious and did not require treatment discontinuation.
CONCLUSIONS
Vedolizumab therapy was not associated with an increased incidence of respiratory tract infection compared with placebo.
Background: Vedolizumab (VDZ) is a safe and effective treatment for moderately to severely active ulcerative colitis and Crohn's disease; however, effects on surgical rates have not yet been evaluated. This study aimed (1) to compare the surgical incidence rates of VDZ and placebo in GEMINI I (ulcerative colitis; NCT00783718) and II (Crohn's disease; NCT00783692) and (2) to describe the surgical incidence rates through year 5 from the GEMINI LTS trial (ulcerative colitis and Crohn's disease; NCT00790933). Methods: Data were pooled from week 6 induction VDZ responders who were randomized to VDZ or placebo maintenance (intent-to-treat maintenance populations) from GEMINI I1 and II,2 and from patients receiving VDZ in the GEMINI LTS trial.3,4 Using the Kaplan-Meier product-limit method, we estimated “time to first surgery” through 1 year (VDZ and placebo groups from GEMINI I and II) and 5 years (VDZ1 and VDZ2 groups from GEMINI LTS [VDZ1=VDZ throughout; VDZ2=placebo from week 6 to 1 year, then VDZ for the LTS study]). Patients without surgery were censored at the last follow-up date through 1 year and 5 years. The log-rank test was used for comparisons between groups. Results: The analysis included 834 patients in total. Mean ages were 40.0 and 35.7 years for patients with ulcerative colitis and Crohn's disease, respectively; proportions of prior tumor necrosis factor antagonist failure were 39.9% and 54.9%, and mean disease duration times were 7.2 and 8.6 years. Figure 1 shows cumulative surgical incidence rates for the study groups, as well as the log-rank comparisons at 1 year (VDZ and placebo groups) and 5 years (VDZ1 and VDZ2 groups). Conclusion: In this population of patients with moderately to severely active ulcerative colitis or Crohn's disease, surgery rates within the first year of observation were lower in patients assigned to VDZ than in those who received placebo, with a significant difference observed in ulcerative colitis. For patients who continued treatment for up to 5 years, VDZ provided long-term benefit in both diseases with low rates of surgical intervention. The post hoc nature of the analysis and the small number of surgical events require further real-world evaluation of the ability of VDZ to reduce surgical rates in patients with ulcerative colitis and Crohn's disease. References 1Feagan BG, et al. N Engl J Med. 2013;369:699-710 2Sandborn WJ, et al. N Engl J Med. 2013;369:711-21 3Loftus EV Jr, et al. J Crohns Colitis. 2017;11:400-11 4Vermeire S, et al. J Crohns Colitis. 2017;11:412-24 [Figure presented]
Background and Aims: This GEMINI 1 post hoc analysis evaluated vedolizumab efficacy for inducing deep remission in patients with ulcerative colitis and correlation between vedolizumab trough concentrations and deep remission rates. Methods: Week 6 vedolizumab responders were re‐randomized to placebo or vedolizumab every 8 or 4 weeks. Deep remission at Week 52 was measured using four different definitions [from most to least stringent]: [1] Mayo Clinic endoscopic score = 0, rectal bleeding score = 0 and decrease or no change from baseline in stool frequency score; [2] endoscopic score ≤1, rectal bleeding score = 0 and stool frequency score = 0; [3] endoscopic score ≤1, rectal bleeding score = 0, decrease or no change from baseline stool frequency score, and total score [endoscopic score + rectal bleeding score + stool frequency score] ≤1; and [4] endoscopic score ≤1, rectal bleeding score = 0 and stool frequency score ≤1. Steady‐state trough vedolizumab serum concentrations were evaluated. Results: At Week 6, 373 vedolizumab responders were re‐randomized to maintenance placebo [n = 126] or vedolizumab every 8 [n = 122] or 4 [n = 125] weeks. Significantly more vedolizumab patients achieved deep remission at Week 52 for the most (placebo 8.7%, every 8 weeks 27.0% [p = 0.0001], every 4 weeks 28.0% [p < 0.0001]) and least (placebo 15.9%, every 8 weeks 43.4% [p < 0.0001], every 4 weeks 43.2% [p < 0.0001]) stringent definitions. Patients with higher vedolizumab trough concentration quartiles had higher deep remission rates [all definitions] compared with those with the lowest quartile or who received placebo. Conclusion: Vedolizumab was associated with significantly higher deep remission rates than placebo at Week 52, regardless of deep remission definition [NCT00783718].
Background: Sustaining clinical remission is an important treatment goal in moderate‐to‐severe UC. This post hoc exploratory analysis assessed the long‐term efficacy of vedolizumab in the subset of patients with UC in the GEMINI 1 study who were in clinical remission by week 14 after 3 induction doses, administered at weeks 0, 2, and 6. Methods: Sustained clinical remission (primary endpoint) was evaluated using 2 definitions: (1) a partial Mayo Score (pMS) of ≤2 with no subscore >1 and (2) a rectal bleeding subscore (RBS) of 0 throughout weeks 14, 26, 38, and 52. Results: The proportion of patients in clinical remission at week 14 was significantly higher in patients receiving vedolizumab (n = 620) compared with placebo (n = 149) (pMS: 32.7% vs 20.1% [percentage‐point difference (Δ) 12.6%; 95% confidence interval [CI], 5.2‐20.0]; RBS: 47.3% vs 28.9% [Δm,18.4%; 95% CI, 10.1‐26.7]). Of patients in clinical remission at week 14, a significantly higher proportion of vedolizumab‐treated patients achieved sustained clinical remission compared with placebo (pMS: 66.5% vs 26.7%; Δ39.8%; 95% CI, 22.7‐56.9; RBS: 56.7% vs 20.9%; Δ35.7%; 95% CI, 22.3‐49.1). Findings were consistent in tumor necrosis factor (TNF) antagonist‐naive and antagonist‐failure patients. Conclusion: Compared with placebo, 35%‐40% more patients receiving a full induction course of vedolizumab had sustained clinical remission after 52 weeks of therapy. This result was observed irrespective of TNF antagonist treatment history. Clinical remission at week 14 may therefore be a predictor for sustained clinical remission with vedolizumab.
BACKGROUND & AIMS: Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). We investigated the time course of clinical response to vedolizumab in patients who were and were not previously treated with tumor necrosis factor (TNF) antagonists.
METHODS: We performed a post-hoc analysis of data from phase 3, randomized, controlled trials of vedolizumab vs placebo in adult patients with UC (N = 374) or CD (N = 784). We collected data on patient-reported symptoms (rectal bleeding and stool frequency for patients with UC, abdominal pain and loose stool frequency for patients with CD) reported at weeks 2, 4, and 6 of treatment. We reported mean percentage score changes from baseline and proportions of patients who achieved predefined scores. We performed multivariate logistic regression analysis to identify factors associated with an early response (at week 2).
RESULTS: In patients with UC (overall or naive to TNF antagonist therapy), a significantly greater percentage of patients given vedolizumab achieved the predefined composite symptom score at weeks 2, 4, and 6 compared to those given placebo. In patients with CD who were naive to TNF antagonists, a significantly greater percentage of patients given vedolizumab achieved the predefined score at weeks 2 and 4 compared to those given placebo. Among patients with UC given vedolizumab, 19.1% (overall) and 22.3% (TNF antagonist naive) achieved a composite score of rectal bleeding of 0 and stool frequency ≤1 at week 2 compared to 10% (overall) and 6.6% (TNF antagonist naive) of those receiving placebo. Among TNF antagonist-naive patients with CD, 15.0% of those given vedolizumab achieved an average daily composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 (compared to 7.9% given placebo), and 23.8% of those given vedolizumab achieved these by week 4 (compared to 10.3% given placebo).
CONCLUSIONS: In a post-hoc analysis of data from phase 3 clinical trials, vedolizumab significantly improved patient-reported symptoms of UC and CD as early as week 2 of treatment, continuing through the first 6 weeks-especially when given as first-line biologic therapy. ClinicalTrials.gov no: NCT00783718, NCT00783692, NCT01224171.
Product Name: VEDOLIZUMAB Product Code: MLN0002 Pharmaceutical Form: Powder for solution for infusion INN or Proposed
INN:
VEDOLIZUMAB CAS Number: 943609‐66‐3 Current Sponsor code: MLN0002 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300mg‐ Pharmaceutical form of the placebo: Solution for infusion Route of administration of the placebo: Intravenous use
CONDITION:
Moderate to Severe Ulcerative Colitis ; MedDRA version: 9.1 Level: LLT Classification code 10045365 Term: Ulcerative colitis
PRIMARY OUTCOME:
Main Objective: Primary Objective for the Induction Phase ; ; • To determine the effect of MLN0002 induction treatment on clinical response at 6 weeks; ; Primary Objective for the Maintenance Phase ; ; • To determine the effect of MLN0002 maintenance treatment on clinical remission at 52 weeks; ; ; ; ; ; Primary end point(s): Primary Endpoint for the Induction Phase:; ; • Proportion of patients with clinical response at Week 6; ; ; Primary Endpoint for the Maintenance Phase:; ; • Proportion of patients in clinical remission at Week 52; ; ; ; ; ; Secondary Objective: Secondary Objectives for the Induction Phase; ; • To determine the effect of MLN0002 induction treatment on clinical remission at 6 weeks; ; • To determine the effect of MLN0002 induction treatment on mucosal healing at 6 weeks; ; ; Secondary Objectives for the Maintenance Phase; ; • To determine the effect of MLN0002 maintenance treatment on durability of clinical response ; ; • To determine the effect of MLN0002 maintenance treatment on mucosal healing at 52 weeks; ; • To determine the effect of MLN0002 maintenance treatment on durability of clinical remission ; ; • To determine the effect of MLN0002 maintenance treatment on corticosteroid‐free remission at 52 weeks; ; ; ; ; ;
INCLUSION CRITERIA:
1. Age 18 to 80 2. Male or female patient who is voluntarily able to give informed consent 3. Female patients must: • be post‐menopausal for at least 1 year before the screening visit, OR • be surgically sterile, OR • (if they are of childbearing potential) agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 6 months after the last dose of study drug, OR • agree to completely abstain from heterosexual contact. Male patients, even if surgically sterilized (ie, status post‐vasectomy), must: • agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, OR • agree to completely abstain from heterosexual contact. 4. Diagnosis of ulcerative colitis established at least 6 months prior to enrollment by clinical and endoscopic evidence and corroborated by a his
