Downloaded from http://gut.bmj.com/ on December 9, 2014 - Published by group.bmj.com
Gut Online First, published on April 24, 2014 as 10.1136/gutjnl-2014-307127 Inflammatory bowel disease
ORIGINAL ARTICLE
Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results Tim Wyant,1 Tim Leach,1 Serap Sankoh,1 Yuemei Wang,1 Jonathan Paolino,2 Marcela F Pasetti,3 Brian G Feagan,4 Asit Parikh5 1
Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA 2 University of Massachusetts Medical School, Worcester, Massachusetts, USA 3 Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA 4 Department of Medicine and Department of Epidemiology and Biostatistics, Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada 5 Takeda Pharmaceuticals International, Inc, Deerfield, Illinois, USA Correspondence to Dr Tim Wyant, Takeda Pharmaceuticals International Co, 40 Landsdowne St, Cambridge, MA 02139, USA; [email protected] Received 25 February 2014 Revised 2 April 2014 Accepted 3 April 2014
ABSTRACT Objective The α4β7 integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated. Design In this randomised, double-blind, placebocontrolled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750 mg (n=64) or placebo (n=63). After 4 days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre ≥10 IU/L). OCV seroconversion at day 74 (>4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point. Results A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) at day 74. A total of 60 (96.8%) placebo-treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs 3007.8 ELISA Units (EU)/mL) and day 32 (11629.3 vs 1575.4 EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo. Conclusions Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action. Trial registration number NCT Number: 01981616; EudraCT Number: 2011-001874-24.
INTRODUCTION
To cite: Wyant T, Leach T, Sankoh S, et al. Gut Published Online First: [please include Day Month Year] doi:10.1136/gutjnl2014-307127
The α4β7 integrin, expressed on leucocyte subpopulations, represents a key determinant of gut mucosal immunity.1 The principal adhesion ligand of α4β7, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), is preferentially expressed on high endothelial venules at sites of lymphocyte extravasation in gastrointestinal mucosa and associated lymphoid tissue. Binding of MAdCAM-1 by lymphocytes expressing activated α4β7 mediates migration of these cells into tissues.2 3 Immunological
Significance of this study What is already known about this subject?
▸ Vedolizumab, a humanised α4β7 integrin monoclonal antibody in development for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD), downregulates gut inflammation by inhibiting intestinal T-lymphocyte trafficking. ▸ Systemic inflammatory bowel disease therapies (corticosteroids, thiopurines, tumour necrosis factor α (TNF-α) antagonists) are associated with increased risk of serious infection. The systemically active anti-α4 integrin therapy natalizumab carries a risk of progressive multifocal leukoencephalopathy, a serious central nervous system viral infection thought to arise from reduced T-cell trafficking to the brain. ▸ Placebo-controlled phase III studies have demonstrated that the overall rates of serious infections were similar in vedolizumab-treated and placebo-treated patients with UC or CD. ▸ Impaired responses to hepatitis B vaccine have been observed in patients treated with TNF-α antagonists.
What are the new findings?
▸ Antibody titres to parenterally administered hepatitis B vaccine did not appreciably differ over time between participants treated with placebo and those treated with vedolizumab. ▸ The overall magnitude of the humoral response to enterically administered oral cholera vaccine was significantly reduced in vedolizumabtreated participants, but not in those who received placebo. ▸ Vedolizumab did not alter the response to parenterally administered antigens, but did reduce the response to oral antigens, supporting the hypothesis that its mechanism of action is selective for the gastrointestinal system.
correlates of antagonising this interaction in humans have not been described previously. Vedolizumab, a humanised monoclonal IgG1 antagonist of the α4β7 integrin currently in development for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD),1 selectively downregulates gut inflammation by inhibiting intestinal T-lymphocyte trafficking.
Wyant T, et al. Gut 2014;0:1–7. 1 Copyright Article authordoi:10.1136/gutjnl-2014-307127 (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from http://gut.bmj.com/ on December 9, 2014 - Published by group.bmj.com
Inflammatory bowel disease
Significance of this study How might it impact on clinical practice in the foreseeable future?
▸ These data support the premise that selective immunomodulatory agents such as vedolizumab hold great promise for the treatment of inflammatory bowel diseases. ▸ Our results are of considerable importance for patients who may be undergoing treatment with vedolizumab and are in need of vaccination, particularly with oral or mucosal vaccines.
Conventional treatments for UC and CD, such as corticosteroids, thiopurines (eg, azathioprine, 6-mercaptopurine) and tumour necrosis factor α (TNF-α) antagonists, act systemically and are associated with an increased risk of serious infection.4–6 Likewise, the safety of the systemically active anti-α4 integrin therapy natalizumab is compromised by the risk of progressive multifocal leukoencephalopathy, a serious central nervous system viral infection that is thought to originate from interference with T-cell trafficking to the brain.7 In contrast, analysis of safety data from placebo-controlled phase III studies of vedolizumab demonstrated that the overall rates of serious infections were similar in vedolizumab-treated and placebo-treated patients. Results from these controlled human studies have suggested benefits of vedolizumab in treating UC and CD.8–11 The mechanism of action of vedolizumab is hypothesised to be restricted to the gastrointestinal tract, not affecting immune responses outside of the gastrointestinal tract, which might be expected to positively affect its safety profile. To test this hypothesis, the current immune challenge study was conducted in healthy participants to assess the immune responses to two specific vaccine series, a hepatitis B vaccine (HBV) (a parenterally administered antigen) and an oral cholera vaccine (OCV) (an enterally administered T-cell-dependent antigen),12 after administration of a single intravenous dose of vedolizumab or placebo. We hypothesised that humoral responses to HBV would be similar between vedolizumab- and placebo-treated participants, whereas responses to OCV would be attenuated with vedolizumab. This gut-selective immune modulation is an intriguing premise that, if achievable, holds great potential as a strategy for the treatment of UC and CD.
MATERIALS AND METHODS Study design The final protocol, amendments and informed consent forms were reviewed and approved by the independent ethics committee at the study site. The study was conducted in compliance with the protocol, Good Clinical Practice guidelines, and applicable regulatory requirements (including the International Conference on Harmonisation guidelines), and in accordance with the ethical principles in the Declaration of Helsinki. Written informed consent was obtained from all participants at the time of enrolment. In this phase I, randomised, double-blind, placebo-controlled, parallel-group, single-centre (ICON Development Solutions, Manchester, UK) non-inferiority study, 127 healthy participants were randomly assigned in a 1:1 ratio to receive a single intravenous dose of vedolizumab 750 mg or placebo. This dose of vedolizumab was chosen to ensure adequate serum drug concentrations and complete α4β7 receptor saturation in peripheral 2
Figure 1 Study design. ⋆, Enrolment and dosing on day 1; a participant was considered to be enrolled in the study when he/she had received any amount of study drug. ▴, Hepatitis B vaccine administered on days 4, 32 and 60. ♦, Cholera vaccine administered on days 4 and 18. ET, early termination.
blood throughout the study period, including key time points (ie, up to day 74). Pharmacodynamic and pharmacokinetic measurements were taken to ensure that adequate levels were achieved. The study included a screening period (days −28 to −1), followed by a treatment period (days 1–60), during which all participants received a single dose of either vedolizumab 750 mg or placebo (day 1), an intramuscular dose of HBV on days 4, 32 and 60, and an oral dose of OCV on days 4 and 18. An observation period (days 61–127) followed treatment (figure 1). Vaccine responses were assessed until day 74. Safety was assessed up to day 127 by monitoring adverse events, vital signs and laboratory variables. Primary and key secondary end points were HBV and OCV seroconversion rates, respectively. For HBV, seroconversion was defined as a serum hepatitis B surface antigen (HBs) antibody concentration of ≥10 IU/L. For OCV, seroconversion was defined as a greater than fourfold increase from baseline in the cholera toxin (CT) antibody titre (IgG, IgM or IgA).13 14 Serum HBs and CT antibody levels were determined on day 1 ( predose) and on days 18, 32, 60 and 74. The primary assessment was conducted on day 74. The total study duration, including screening, was 5 months.
Participants Eligible participants were healthy men or women between the ages of 18 and 39 years with a body mass index between 18 and 32 kg/m2, inclusive. Individuals were excluded if they had: known exposure to hepatitis B virus; known prior hepatitis B vaccination irrespective of the number of doses received or previous employment in a healthcare setting; seropositivity for prior hepatitis B infection or hepatitis B vaccination during the screening period; or known exposure to cholera or prior OCV exposure irrespective of the number of doses received.
Randomisation and masking Participants were allocated to treatment using blocked randomisation (block size of 2). Randomisation was centralised using an interactive voice response system. Investigational pharmacy staff members were the only site personnel who were aware of the treatment assignment. All other study site personnel and the study participants were blinded.
Vaccines The HBV (HBvaxPRO; Sanofi Pasteur MSD, Maidenhead, Berkshire, UK) is an intramuscular recombinant component vaccine approved for use in the European Union and elsewhere.15 The OCV (Dukoral; Crucell Vaccines, Toronto, Ontario, Canada (a division of Janssen)) is a combination of killed bacterial cells and the recombinant B subunit of the CT that is approved in some European countries and Canada for the prevention of traveller’s diarrhoea.16 Wyant T, et al. Gut 2014;0:1–7. doi:10.1136/gutjnl-2014-307127
Downloaded from http://gut.bmj.com/ on December 9, 2014 - Published by group.bmj.com
Inflammatory bowel disease Assessment of immune response Blood samples were collected for assessment of the immune response in serum to the vaccines at screening (HBs antibodies) on day 1 ( predose; CT antibodies) and on days 18, 32, 60 and 74 (HBs and CT antibodies). Faecal and saliva samples were obtained for assessment of secretory IgA on day 1 ( predose) and on days 18, 32 and 60; an additional saliva sample for assessment of secretory IgA was collected on day 74.
Pharmacokinetic/pharmacodynamic assessments Blood samples for the determination of serum vedolizumab concentrations were collected on day 1 ( pre- and post-dose) and on days 18, 32, 60, 74 and 127. Serum vedolizumab concentrations were measured using an ELISA. Blood samples for the determination of MAdCAM-1-Fc binding (indicative of the extent of cellular α4β7 integrin binding by vedolizumab) were collected on day 1 ( predose) and on days 4, 18, 32, 60, 74 and 127. This binding was analysed using soluble MAdCAM-1-Fc and detected by flow cytometry using a fluorescently labelled antimouse Fc.
Statistical analysis Sample size was calculated to demonstrate a non-inferiority margin of 15% with the lower bound of the one-sided 95% CI for the difference in the proportions of participants with HBV seroconversion between the vedolizumab and placebo groups, assuming a 90% seroconversion rate. Assuming a 90% evaluability rate, up to 125 participants were needed for randomisation (table 1). For the primary objective, to determine the effect of vedolizumab on the immune response to HBV at day 74, a point estimate and 95% CI for the between-group difference in the proportions of participants having an immune response were obtained for the per-protocol population. The lower bound of the 95% CI was compared with the prespecified non-inferiority margin of −15%. The same analysis was performed for the key secondary objective, to determine the effect of vedolizumab on the immune response to OCV at day 74 (table 1).
RESULTS Participant disposition and baseline characteristics The trial was conducted from 13 September 2011 to 13 July 2012. Of 332 healthy individuals screened for eligibility, 127 were randomly assigned to receive a single intravenous dose of either placebo (n=63) or vedolizumab 750 mg (n=64) (figure 2). A total of 125 participants completed the study; one participant in the placebo group was withdrawn from the study because of an adverse event (injury to skin on the elbow), and one participant in the vedolizumab group was withdrawn because of protocol deviations ( participant was unable to attend further study visits after study drug dosing). Four participants were excluded
from the per-protocol analysis because of protocol deviations. Reasons for exclusion were non-receipt of either vaccine as scheduled (n=1 each for placebo and vedolizumab) and non-measurable serum vedolizumab concentration at day 74 (n=2 for vedolizumab). Treatment groups were generally similar with regard to demographic and other baseline characteristics (table 2).
Serum vedolizumab concentrations and α4β7 saturation The mean serum vedolizumab concentration in vedolizumabtreated participants was 20.1 mg/mL at day 74 (figure 3). This concentration of vedolizumab was associated with maximal saturation of α4β7 on peripheral blood CD4+CD45RO+ T cells (figure 3).
Immune responses to HBV and OCV Of the 123 participants who received study drug and were included in the per-protocol population analysis, 56 of 62 (90.3%) in the placebo group and 54 of 61 (88.5%) in the vedolizumab group showed HBV seroconversion at day 74 (absolute difference, −1.8%; 95% CI −12.7% to 9.1%). Because the lower bound of the 95% CI is contained within the prespecified margin of −15%, the non-inferiority criterion was met for this end point. The time course of serum IgG response to HBV, as gauged by HBs antibody titres, is shown in figure 4A. The HBs antibody titres did not appreciably differ over time between the placebo group (median area under the concentration–time curve (AUC)day 1–74=1598 IU/L/day) and the vedolizumab group (median AUCday 1–74=2116 IU/L/day) ( p=0.99; Wilcoxon twosample test). At day 74, 2 weeks after the final immunisation, geometric mean (% coefficient of variation) HBs antibody titres were 114.4 (539.6) IU/L and 129.6 (359.3) IU/L for the placebo and vedolizumab groups, respectively. In contrast with HBV (for which the accepted standard for protective immunity is an initial serum HBs antibody titre of >10 IU/L),17 OCV is not associated with an accepted clinical standard of protective immunity; however, an increase from baseline of more than fourfold in IgM, IgA or IgG levels is considered a positive vaccine response.13 14 At day 74, OCV response rates for all evaluable participants were 96.8% and 82.5% in the placebo and vedolizumab groups, respectively (absolute difference −14.2%; 95% CI −24.6% to −3.9%). The entire 95% CI for the difference excludes 0, whereas the lower bound falls outside the prespecified margin of −15%; thus, OCV response in vedolizumab-treated participants did not meet the non-inferiority criterion. Time courses of serum IgG and IgA responses to OCV are shown in figures 4B, C respectively. Although the percentage of OCV responders was not markedly different between treatment groups, the overall magnitude of the humoral response was significantly reduced in vedolizumab-treated participants. The AUCday 1–74 analyses showed significant differences between the vedolizumab and
Table 1 Power estimates for primary and key secondary efficacy analyses Objective
End point at day 74 vedolizumab vs placebo
Assumed response rate
Sample size*
Power (%)
Primary
HBV seroconversion OCV seroconversion
Placebo: 55† Vedolizumab: 55 Placebo: 55 Vedolizumab: 55
80
Key secondary
Placebo: 90% Vedolizumab: 90% Placebo: 85% Vedolizumab: 85%
71
*One-sided test based on binomial non-inferiority trials, significance level (α)=0.05, non-inferiority margin=0.15. †Assuming 90% evaluability rate. HBV, hepatitis B vaccine; OCV, oral cholera vaccine.
Wyant T, et al. Gut 2014;0:1–7. doi:10.1136/gutjnl-2014-307127
3
Downloaded from http://gut.bmj.com/ on December 9, 2014 - Published by group.bmj.com
Inflammatory bowel disease Figure 2 Participant flow diagram. Completed all day 127 assessments. b All participants who received any amount of blinded study drug based on what they actually received. cAll participants without any major protocol deviations. a
placebo groups for both serum IgG (median AUCday 1–74=124 384 and 736 610 titre·day, respectively) and serum IgA (median AUCday 1–74=42 952 and 118 868 titre·day, respectively) (both p
Gut Online First, published on April 24, 2014 as 10.1136/gutjnl-2014-307127 Inflammatory bowel disease
ORIGINAL ARTICLE
Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results Tim Wyant,1 Tim Leach,1 Serap Sankoh,1 Yuemei Wang,1 Jonathan Paolino,2 Marcela F Pasetti,3 Brian G Feagan,4 Asit Parikh5 1
Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA 2 University of Massachusetts Medical School, Worcester, Massachusetts, USA 3 Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA 4 Department of Medicine and Department of Epidemiology and Biostatistics, Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada 5 Takeda Pharmaceuticals International, Inc, Deerfield, Illinois, USA Correspondence to Dr Tim Wyant, Takeda Pharmaceuticals International Co, 40 Landsdowne St, Cambridge, MA 02139, USA; [email protected] Received 25 February 2014 Revised 2 April 2014 Accepted 3 April 2014
ABSTRACT Objective The α4β7 integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated. Design In this randomised, double-blind, placebocontrolled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750 mg (n=64) or placebo (n=63). After 4 days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre ≥10 IU/L). OCV seroconversion at day 74 (>4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point. Results A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) at day 74. A total of 60 (96.8%) placebo-treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs 3007.8 ELISA Units (EU)/mL) and day 32 (11629.3 vs 1575.4 EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo. Conclusions Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action. Trial registration number NCT Number: 01981616; EudraCT Number: 2011-001874-24.
INTRODUCTION
To cite: Wyant T, Leach T, Sankoh S, et al. Gut Published Online First: [please include Day Month Year] doi:10.1136/gutjnl2014-307127
The α4β7 integrin, expressed on leucocyte subpopulations, represents a key determinant of gut mucosal immunity.1 The principal adhesion ligand of α4β7, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), is preferentially expressed on high endothelial venules at sites of lymphocyte extravasation in gastrointestinal mucosa and associated lymphoid tissue. Binding of MAdCAM-1 by lymphocytes expressing activated α4β7 mediates migration of these cells into tissues.2 3 Immunological
Significance of this study What is already known about this subject?
▸ Vedolizumab, a humanised α4β7 integrin monoclonal antibody in development for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD), downregulates gut inflammation by inhibiting intestinal T-lymphocyte trafficking. ▸ Systemic inflammatory bowel disease therapies (corticosteroids, thiopurines, tumour necrosis factor α (TNF-α) antagonists) are associated with increased risk of serious infection. The systemically active anti-α4 integrin therapy natalizumab carries a risk of progressive multifocal leukoencephalopathy, a serious central nervous system viral infection thought to arise from reduced T-cell trafficking to the brain. ▸ Placebo-controlled phase III studies have demonstrated that the overall rates of serious infections were similar in vedolizumab-treated and placebo-treated patients with UC or CD. ▸ Impaired responses to hepatitis B vaccine have been observed in patients treated with TNF-α antagonists.
What are the new findings?
▸ Antibody titres to parenterally administered hepatitis B vaccine did not appreciably differ over time between participants treated with placebo and those treated with vedolizumab. ▸ The overall magnitude of the humoral response to enterically administered oral cholera vaccine was significantly reduced in vedolizumabtreated participants, but not in those who received placebo. ▸ Vedolizumab did not alter the response to parenterally administered antigens, but did reduce the response to oral antigens, supporting the hypothesis that its mechanism of action is selective for the gastrointestinal system.
correlates of antagonising this interaction in humans have not been described previously. Vedolizumab, a humanised monoclonal IgG1 antagonist of the α4β7 integrin currently in development for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD),1 selectively downregulates gut inflammation by inhibiting intestinal T-lymphocyte trafficking.
Wyant T, et al. Gut 2014;0:1–7. 1 Copyright Article authordoi:10.1136/gutjnl-2014-307127 (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from http://gut.bmj.com/ on December 9, 2014 - Published by group.bmj.com
Inflammatory bowel disease
Significance of this study How might it impact on clinical practice in the foreseeable future?
▸ These data support the premise that selective immunomodulatory agents such as vedolizumab hold great promise for the treatment of inflammatory bowel diseases. ▸ Our results are of considerable importance for patients who may be undergoing treatment with vedolizumab and are in need of vaccination, particularly with oral or mucosal vaccines.
Conventional treatments for UC and CD, such as corticosteroids, thiopurines (eg, azathioprine, 6-mercaptopurine) and tumour necrosis factor α (TNF-α) antagonists, act systemically and are associated with an increased risk of serious infection.4–6 Likewise, the safety of the systemically active anti-α4 integrin therapy natalizumab is compromised by the risk of progressive multifocal leukoencephalopathy, a serious central nervous system viral infection that is thought to originate from interference with T-cell trafficking to the brain.7 In contrast, analysis of safety data from placebo-controlled phase III studies of vedolizumab demonstrated that the overall rates of serious infections were similar in vedolizumab-treated and placebo-treated patients. Results from these controlled human studies have suggested benefits of vedolizumab in treating UC and CD.8–11 The mechanism of action of vedolizumab is hypothesised to be restricted to the gastrointestinal tract, not affecting immune responses outside of the gastrointestinal tract, which might be expected to positively affect its safety profile. To test this hypothesis, the current immune challenge study was conducted in healthy participants to assess the immune responses to two specific vaccine series, a hepatitis B vaccine (HBV) (a parenterally administered antigen) and an oral cholera vaccine (OCV) (an enterally administered T-cell-dependent antigen),12 after administration of a single intravenous dose of vedolizumab or placebo. We hypothesised that humoral responses to HBV would be similar between vedolizumab- and placebo-treated participants, whereas responses to OCV would be attenuated with vedolizumab. This gut-selective immune modulation is an intriguing premise that, if achievable, holds great potential as a strategy for the treatment of UC and CD.
MATERIALS AND METHODS Study design The final protocol, amendments and informed consent forms were reviewed and approved by the independent ethics committee at the study site. The study was conducted in compliance with the protocol, Good Clinical Practice guidelines, and applicable regulatory requirements (including the International Conference on Harmonisation guidelines), and in accordance with the ethical principles in the Declaration of Helsinki. Written informed consent was obtained from all participants at the time of enrolment. In this phase I, randomised, double-blind, placebo-controlled, parallel-group, single-centre (ICON Development Solutions, Manchester, UK) non-inferiority study, 127 healthy participants were randomly assigned in a 1:1 ratio to receive a single intravenous dose of vedolizumab 750 mg or placebo. This dose of vedolizumab was chosen to ensure adequate serum drug concentrations and complete α4β7 receptor saturation in peripheral 2
Figure 1 Study design. ⋆, Enrolment and dosing on day 1; a participant was considered to be enrolled in the study when he/she had received any amount of study drug. ▴, Hepatitis B vaccine administered on days 4, 32 and 60. ♦, Cholera vaccine administered on days 4 and 18. ET, early termination.
blood throughout the study period, including key time points (ie, up to day 74). Pharmacodynamic and pharmacokinetic measurements were taken to ensure that adequate levels were achieved. The study included a screening period (days −28 to −1), followed by a treatment period (days 1–60), during which all participants received a single dose of either vedolizumab 750 mg or placebo (day 1), an intramuscular dose of HBV on days 4, 32 and 60, and an oral dose of OCV on days 4 and 18. An observation period (days 61–127) followed treatment (figure 1). Vaccine responses were assessed until day 74. Safety was assessed up to day 127 by monitoring adverse events, vital signs and laboratory variables. Primary and key secondary end points were HBV and OCV seroconversion rates, respectively. For HBV, seroconversion was defined as a serum hepatitis B surface antigen (HBs) antibody concentration of ≥10 IU/L. For OCV, seroconversion was defined as a greater than fourfold increase from baseline in the cholera toxin (CT) antibody titre (IgG, IgM or IgA).13 14 Serum HBs and CT antibody levels were determined on day 1 ( predose) and on days 18, 32, 60 and 74. The primary assessment was conducted on day 74. The total study duration, including screening, was 5 months.
Participants Eligible participants were healthy men or women between the ages of 18 and 39 years with a body mass index between 18 and 32 kg/m2, inclusive. Individuals were excluded if they had: known exposure to hepatitis B virus; known prior hepatitis B vaccination irrespective of the number of doses received or previous employment in a healthcare setting; seropositivity for prior hepatitis B infection or hepatitis B vaccination during the screening period; or known exposure to cholera or prior OCV exposure irrespective of the number of doses received.
Randomisation and masking Participants were allocated to treatment using blocked randomisation (block size of 2). Randomisation was centralised using an interactive voice response system. Investigational pharmacy staff members were the only site personnel who were aware of the treatment assignment. All other study site personnel and the study participants were blinded.
Vaccines The HBV (HBvaxPRO; Sanofi Pasteur MSD, Maidenhead, Berkshire, UK) is an intramuscular recombinant component vaccine approved for use in the European Union and elsewhere.15 The OCV (Dukoral; Crucell Vaccines, Toronto, Ontario, Canada (a division of Janssen)) is a combination of killed bacterial cells and the recombinant B subunit of the CT that is approved in some European countries and Canada for the prevention of traveller’s diarrhoea.16 Wyant T, et al. Gut 2014;0:1–7. doi:10.1136/gutjnl-2014-307127
Downloaded from http://gut.bmj.com/ on December 9, 2014 - Published by group.bmj.com
Inflammatory bowel disease Assessment of immune response Blood samples were collected for assessment of the immune response in serum to the vaccines at screening (HBs antibodies) on day 1 ( predose; CT antibodies) and on days 18, 32, 60 and 74 (HBs and CT antibodies). Faecal and saliva samples were obtained for assessment of secretory IgA on day 1 ( predose) and on days 18, 32 and 60; an additional saliva sample for assessment of secretory IgA was collected on day 74.
Pharmacokinetic/pharmacodynamic assessments Blood samples for the determination of serum vedolizumab concentrations were collected on day 1 ( pre- and post-dose) and on days 18, 32, 60, 74 and 127. Serum vedolizumab concentrations were measured using an ELISA. Blood samples for the determination of MAdCAM-1-Fc binding (indicative of the extent of cellular α4β7 integrin binding by vedolizumab) were collected on day 1 ( predose) and on days 4, 18, 32, 60, 74 and 127. This binding was analysed using soluble MAdCAM-1-Fc and detected by flow cytometry using a fluorescently labelled antimouse Fc.
Statistical analysis Sample size was calculated to demonstrate a non-inferiority margin of 15% with the lower bound of the one-sided 95% CI for the difference in the proportions of participants with HBV seroconversion between the vedolizumab and placebo groups, assuming a 90% seroconversion rate. Assuming a 90% evaluability rate, up to 125 participants were needed for randomisation (table 1). For the primary objective, to determine the effect of vedolizumab on the immune response to HBV at day 74, a point estimate and 95% CI for the between-group difference in the proportions of participants having an immune response were obtained for the per-protocol population. The lower bound of the 95% CI was compared with the prespecified non-inferiority margin of −15%. The same analysis was performed for the key secondary objective, to determine the effect of vedolizumab on the immune response to OCV at day 74 (table 1).
RESULTS Participant disposition and baseline characteristics The trial was conducted from 13 September 2011 to 13 July 2012. Of 332 healthy individuals screened for eligibility, 127 were randomly assigned to receive a single intravenous dose of either placebo (n=63) or vedolizumab 750 mg (n=64) (figure 2). A total of 125 participants completed the study; one participant in the placebo group was withdrawn from the study because of an adverse event (injury to skin on the elbow), and one participant in the vedolizumab group was withdrawn because of protocol deviations ( participant was unable to attend further study visits after study drug dosing). Four participants were excluded
from the per-protocol analysis because of protocol deviations. Reasons for exclusion were non-receipt of either vaccine as scheduled (n=1 each for placebo and vedolizumab) and non-measurable serum vedolizumab concentration at day 74 (n=2 for vedolizumab). Treatment groups were generally similar with regard to demographic and other baseline characteristics (table 2).
Serum vedolizumab concentrations and α4β7 saturation The mean serum vedolizumab concentration in vedolizumabtreated participants was 20.1 mg/mL at day 74 (figure 3). This concentration of vedolizumab was associated with maximal saturation of α4β7 on peripheral blood CD4+CD45RO+ T cells (figure 3).
Immune responses to HBV and OCV Of the 123 participants who received study drug and were included in the per-protocol population analysis, 56 of 62 (90.3%) in the placebo group and 54 of 61 (88.5%) in the vedolizumab group showed HBV seroconversion at day 74 (absolute difference, −1.8%; 95% CI −12.7% to 9.1%). Because the lower bound of the 95% CI is contained within the prespecified margin of −15%, the non-inferiority criterion was met for this end point. The time course of serum IgG response to HBV, as gauged by HBs antibody titres, is shown in figure 4A. The HBs antibody titres did not appreciably differ over time between the placebo group (median area under the concentration–time curve (AUC)day 1–74=1598 IU/L/day) and the vedolizumab group (median AUCday 1–74=2116 IU/L/day) ( p=0.99; Wilcoxon twosample test). At day 74, 2 weeks after the final immunisation, geometric mean (% coefficient of variation) HBs antibody titres were 114.4 (539.6) IU/L and 129.6 (359.3) IU/L for the placebo and vedolizumab groups, respectively. In contrast with HBV (for which the accepted standard for protective immunity is an initial serum HBs antibody titre of >10 IU/L),17 OCV is not associated with an accepted clinical standard of protective immunity; however, an increase from baseline of more than fourfold in IgM, IgA or IgG levels is considered a positive vaccine response.13 14 At day 74, OCV response rates for all evaluable participants were 96.8% and 82.5% in the placebo and vedolizumab groups, respectively (absolute difference −14.2%; 95% CI −24.6% to −3.9%). The entire 95% CI for the difference excludes 0, whereas the lower bound falls outside the prespecified margin of −15%; thus, OCV response in vedolizumab-treated participants did not meet the non-inferiority criterion. Time courses of serum IgG and IgA responses to OCV are shown in figures 4B, C respectively. Although the percentage of OCV responders was not markedly different between treatment groups, the overall magnitude of the humoral response was significantly reduced in vedolizumab-treated participants. The AUCday 1–74 analyses showed significant differences between the vedolizumab and
Table 1 Power estimates for primary and key secondary efficacy analyses Objective
End point at day 74 vedolizumab vs placebo
Assumed response rate
Sample size*
Power (%)
Primary
HBV seroconversion OCV seroconversion
Placebo: 55† Vedolizumab: 55 Placebo: 55 Vedolizumab: 55
80
Key secondary
Placebo: 90% Vedolizumab: 90% Placebo: 85% Vedolizumab: 85%
71
*One-sided test based on binomial non-inferiority trials, significance level (α)=0.05, non-inferiority margin=0.15. †Assuming 90% evaluability rate. HBV, hepatitis B vaccine; OCV, oral cholera vaccine.
Wyant T, et al. Gut 2014;0:1–7. doi:10.1136/gutjnl-2014-307127
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Inflammatory bowel disease Figure 2 Participant flow diagram. Completed all day 127 assessments. b All participants who received any amount of blinded study drug based on what they actually received. cAll participants without any major protocol deviations. a
placebo groups for both serum IgG (median AUCday 1–74=124 384 and 736 610 titre·day, respectively) and serum IgA (median AUCday 1–74=42 952 and 118 868 titre·day, respectively) (both p
