A phase II, Multicentre, Randomised, Double-Blind, Placebo-controlled Study to Evaluate Safety, Tolerability, and Efficacy of Amiselimod in Patients with Moderate to Severe Active Crohn’s Disease

Abstract

Background and Aims

Amiselimod is an oral selective S1P₁ receptor modulator with potentially fewer adverse effects than fingolimod. We evaluated the safety, tolerability, and clinical efficacy of amiselimod in participants with moderate to severe active Crohn’s disease.

Methods

This was a phase IIa, multicentre, randomised, double-blind, parallel group, placebo-controlled study comparing amiselimod 0.4 mg with placebo over a 14-Week treatment period. The primary endpoint of the study was the proportion of participants with clinical response (Crohn’s Disease activity Index [CDAI] 100) from baseline at Week 12.

Results

A total of 180 patients were screened and 78 were randomised [40 to amiselimod 0.4 mg and 38 to placebo]. There was no significant difference in the proportion of patients achieving CDAI 100 at Week 12 on amiselimod 0.4 mg and on placebo [48.7% vs. 54.1%, respectively] (odds ratio [OR] [95% confidence interval]: 0.79 [0.31, 1.98]). The results from the secondary endpoint analyses supported the results of the primary endpoint analysis. Treatment with amiselimod 0.4 mg was generally well tolerated, with 71.8% of participants completing the 14-week treatment period. Seven participants had serious adverse events and four discontinued treatment in the amiselimod group.

Conclusions

Amiselimod 0.4 mg for 12 weeks was not superior to placebo for the induction of clinical response [CDAI 100] in Crohn’s disease. Treatment with amiselimod 0.4 mg was generally well tolerated and no new safety concerns related to amiselimod were reported in this study.

1. Introduction

Crohn’s disease [CD] is an idiopathic, chronic inflammatory disease that can affect the entire gastrointestinal tract. The incidence of CD is rising.^1,2 Medical treatment of CD includes glucocorticosteroids, immunosuppressant drugs, and antibodies against tumour necrosis factor [TNF], interleukin [IL]12/23, and integrins. When medical treatment is unsuccessful or when complications develop, surgery is often indicated. Nonetheless, new treatment options for CD are badly needed. Ongoing research efforts focus on JAK inhibitors and novel trafficking blockers such as etrolizumab, ontolizumab, and several sphingosine-1-phosphate [S1P] receptor modulators. Ozanimod and etrasimod are two molecules shown to be effective for the treatment of ulcerative colitis in phase 2 trials.

Amiselimod {MT-1303; 2-Amino-2-{2-[4-[heptyloxy]-3-[trifluoromethyl]phenyl]ethyl} propane-1,3-diol hydrochloride) is an oral selective sphingosine 1-phosphate [S1P] receptor modulator, that is effectively converted in vivo into its active metabolite, ([S]-enantiomer of amiselimod-P [[S]-amiselimod-P), a potent and selective S1P receptor modulator.³

Sphingosine-1-phosphate, a multifunctional phospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five types of G protein-coupled S1P receptors [S1P₁, S1P₂, S1P₃, S1P₄, and S1P₅ receptors].^4,5 It has been well documented that S1P and the S1P₁ receptor play an essential role in lymphocyte egress from secondary lymphoid organs.^4,5

S1P receptor modulators are also being investigated for multiple sclerosis. Fingolimod [FTY720] was the first-in-class S1P receptor modulator and received first approval for relapsing-remitting multiple sclerosis [MS].^6–8 The safety profile of fingolimod includes first-dose related bradycardia.⁹ Amiselimod is more selective for the S1P1 and it demonstrated a more favourable cardiac safety profile compared with fingolimod when administered over 28 days in healthy participants.¹⁰

Amiselimod was tested in an animal model of inflammatory bowel disease to evaluate its effect in a severe combined immunodeficiency murine colitis model which is induced by adoptive transfer of CD4+CD45RB^high T cells from BALB/c mice. In this study, amiselimod inhibited the development of chronic colitis in mice, and its inhibitory efficacy was comparable to that of an anti-mouse TNF-α antibody.¹¹ All data taken together warranted further investigation of amiselimod in human participants with CD.

2. Methods

2.1. Study design and participants

This phase IIa, multicentre, randomised, double-blind, placebo-controlled study was designed as an initial evaluation of the safety, tolerability, and clinical efficacy of amiselimod in moderate to severe active Crohn’s disease [CD].¹² Protocol synopsis is available as Supplementary Data 1, available at ECCO-JCC online. For that purpose, amiselimod 0.4 mg once daily for 14 weeks was compared with placebo. The study design is given in Figure 1. Although steady-state plasma concentrations were not expected to be reached until about 10 weeks of treatment, due to the long half-life of amiselimod, lymphocyte reduction at a 0.4-mg dose level was expected to be most pronounced at an earlier time point [from Week 4 onwards]. The PK/PD Sigmoid E_max Model was applied to predict the maximal pharmacodynamic [PD] effect [i.e., the maximal peripheral lymphocyte reduction from baseline] at the steady state of multiple dosing with amiselimod. Based on this model, a dose of 0.4 mg amiselimod was selected for this proof-of-concept study. At 0.4 mg, an absolute nadir value for lymphocyte count was predicted to be approximately 600/μL. This trial enrolled patients in 36 centres in Europe and Japan beginning March 23, 2015, and the last follow-up assessment was on October 10, 2016.

Participants were males or females aged 18 to 65 years [inclusive] with moderate to severe active CD, defined by a CD Activity Index [CDAI] ≥220 to ≤450. The CDAI is a composite index which is composed of various sub-scores including number of liquid/very soft tools, abdominal pain, general well-being, extra-intestinal manifestations, use of anti-diarrhoeal agents, abdominal mass, haematocrit value, and body weight. The diagnosis of CD was confirmed by both endoscopy and histopathology at least 3 months prior to screening. Participants also needed to have an elevated serum C-reactive protein [CRP ≥ 5 mg/L] and/or faecal calprotectin [≥250 μg/g] at screening and had previously used glucocorticosteroids, immunosuppressants, and/or anti-TNFα agents for treatment of CD.

The study consisted of a Screening Period of up to 4 weeks, a 14-week Treatment Period, and a 12-week Follow-up Period, during which there were 10 scheduled visits. Following the initial Screening visit, eligible participants were randomly assigned to receive amiselimod 0.4 mg/day or matching placebo in a 1:1 ratio. Participants who completed the 14-week placebo-controlled Treatment Period had the option to enter a 36-week open-label extension study [MT-1303-E14^13].

The following background therapies were permitted during the study at stable doses: oral 5-aminosalicylic acid, oral glucocorticosteroids, antibiotics, or non-parenteral nutrition therapy. If participants receiving oral corticosteroids had completed all assessments at Week 12 of treatment, glucocorticosteroid tapering was permitted at the discretion of the investigators.

Randomisation was performed centrally using an Interactive Web-based Response System and was stratified according to region [Europe or Japan] and previous exposure to anti-TNFα agents. To avoid the risk of bias, lymphocyte and white blood cell counts were not disclosed to any study personnel or to the treating physicians [except screening and baseline] unless they exceeded pre-specified safety limits [i.e., lymphocyte count <0.20 × 10⁹/L]. An independent unblinded monitor was assigned and had ultimate responsibility for monitoring lymphocyte counts of all participants and for reviewing all these data on an ongoing basis.

The primary endpoint of this study was the proportion of patients with a clinical response defined as a 100-point decrease from baseline in the CDAI score [CDAI 100] at Week 12. Secondary efficacy endpoints included the proportion of participants who achieved a 70-point decrease from baseline in CDAI score [CDAI 70] and the proportion of participants who achieved CDAI 100 at other protocol scheduled visits; the proportion of participants who achieved clinical remission [CDAI score of <150]; and change from baseline in CDAI score. The pharmacokinetic endpoint was the plasma concentration of amiselimod and its active metabolite amiselimod-P. Pharmacodynamic endpoints included lymphocyte counts and lymphocyte subsets.

Exploratory endpoints included time to clinical remission, time to clinical response of CDAI 100 and CDAI 70, change in CDAI sub-scores compared with baseline, CRP, and faecal calprotectin values, and changes from baseline. Safety endpoints included incidence and severity of adverse events [AEs]; physical examination; 12-lead electrocardiogram [ECG] parameters; 24-h/48-h Holter ECG parameters; vital signs; safety laboratory parameters; ophthalmological evaluation; optical coherence tomography. Pulse rate, blood pressure, and 12-lead ECG were measured before dosing and at every hour during the initial 6-h period following the first dose of study medication.

An independent Data Safety Monitoring Board [DSMB] was established in this study. The DSMB scope was to review the study data to ensure the safety of participants enrolled in the study, independent from the sponsor. The operating procedures of the DSMB were based on and were in compliance with the Food and Drug Administration’s ‘Guidance for Clinical Trial Sponsors [on the] Establishment and Operation of Clinical Trial Data Monitoring Committees’ [March 2006 OMB Control No. 0910-0581] and with the European Medicines Agency’s ‘Guideline Data Monitoring Committees’ [January 2006, EMEA/CHMP/EWP/5872/03 Corr].

2.2. Statistical analysis

Given the absence of preliminary data, the sample size for this trial was not based on statistical power calculations but was estimated to be sufficient for an initial evaluation of the efficacy and safety in the investigated population. Statistical analysis was performed using SAS Version 9.2 or later.

The primary endpoint was analysed by fitting a logistic regression model with treatment as fixed effect and baseline CDAI score and previous exposure to anti-TNF agents as covariates using non-responder imputation [NRI] on the intent-to-treat [ITT] population. The odds ratio [OR] of active treatment group versus placebo, with 95% confidence interval [CI] was provided. Secondary efficacy endpoints were analysed as repeated measures using generalised estimating equations. CDAI scores as a continuous endpoint were analysed using a mixed model for repeated measures.

Sub-groups [i.e., use of previous anti-TNF agents, use of oral corticosteroid at baseline] were also analysed as exploratory endpoints. Amiselimod and amiselimod-P concentrations were summarised at each nominal time point, using descriptive statistics and on a linear/linear plot. Amiselimod and amiselimod-P trough concentrations in plasma were summarised from Visit 3 [Week 2] to Visit 7 [Week 14] by treatment group and scheduled sampling time. Lymphocyte counts and lymphocyte subset were summarised using descriptive statistics by treatment group and for each scheduled visit. All safety and tolerability variables were listed and summarised descriptively or using frequency tables where appropriate.

The study was conducted in accordance with the 2013 [Fortaleza] revision of the 1964 Declaration of Helsinki, Good Clinical Practice [GCP] as required by the International Council for Harmonisation [ICH] guidelines. All necessary approvals were received from central or local independent ethics committees.

3. Results

3.1. Participant disposition

A total of 180 participants were screened, of whom 78 participants were randomised in the 11 countries [Supplementary Data 2, available at ECCO-JCC online]. The main reason for screen failure was related to laboratory findings [Supplementary Data 3, available at ECCO-JCC online]. Forty participants were assigned to amiselimod 0.4 mg, and 38 participants were assigned to placebo [Figure 2].

The majority of randomised participants [61/78, 78.2%] completed the 14-week treatment period, among whom 46 participants [59.0%] entered the MT-1303-E14 extension study, 11 participants [14.1%] moved into the Follow-up Period, and four participants [5.1%] did not enter MT-1303-E14 or the Follow-up Period. The ITT population consisted of 76 participants [two participants were excluded: one patient never started treatment and in one patient no CDAI recording on treatment was available].

Withdrawal from the study occurred more often in the amiselimod group (11 participants [27.5%]) than in the placebo group (five participants [13.2%]). The main reasons for withdrawal were withdrawal by the participant (six participants [7.7%]), AE (five participants [6.4%]) and lack of efficacy (four participants [5.1%]), each of which was more frequently seen in the amiselimod group than on placebo. The percentage of participants who are completed by country is provided in Supplementary Data 2.

3.2. Participants

For all participants in the ITT population, demographic and baseline characteristics were similar across the placebo and amiselimod groups. Participant demographics are presented in Table 1. The mean (standard deviation [SD]) body weight and body mass index [BMI] at baseline were 68.42 kg [17.30] and 22.75 kg/m² [4.51], respectively.

Baseline CDAI scores [SD] were comparable between the treatment groups (307.0 [63.2] and 305.1 [50.7] in the placebo and amiselimod 0.4-mg groups, respectively). No notable differences were observed in CRP and faecal calprotectin values at baseline. The median duration of CD was slightly longer in amiselimod 0.4 mg group [8.25 years] than the placebo group [6.86 years]. Overall, the location of CD was similar between treatment groups, the most frequent location being ileocolitis [56.4% in amiselimod 0.4-mg group and 43.2% in placebo group]. Prior use of anti-TNF agents was similar between the two groups overall. Prior use of immunosuppressants was more frequently reported in the placebo group; by contrast, prior use of antibiotics was more frequent in the amiselimod 0.4-mg group.

Concomitant medications for the treatment of CD were generally well balanced between two treatment groups. Concomitant use of oral corticosteroids and aminosalicylates was similar between two groups. Concomitant use of antibiotics was only reported in the amiselimod 0.4-mg group (eight participants [20.5%]), but among those, three participants had received antibiotics as ‘rescue medication’ after randomisation.

3.3. Efficacy evaluations

For the primary endpoint of clinical response at Week 12, there was a slightly greater proportion of participants who achieved CDAI 100 in the placebo group (20 participants [54.1%]) compared with the amiselimod group (19 participants [48.7%]). The odds ratio was smaller than 1 [0.79]; however, the ratio showed a wide range of 95% CIs [0.31, 1.98] and included 1, and therefore no difference was observed between the two groups [Table 2].

A greater proportion of participants achieved CDAI 70 and clinical remission [CDAI <150] at Visit 6 [Week 12] in the placebo group than in the amiselimod 0.4-mg group [64.9% vs. 53.8% and 40.5% vs. 28.2%, respectively] [Figures 3, 4, and 5].

Looking longitudinally, the placebo group showed higher proportions of participants achieving CDAI 100 response, CDAI 70 response, and clinical remission at all visits, except for Visit 3 [Week 2] [Figures 3–5]. The odds ratios for CDAI 100, CDAI 70, and clinical remission at each scheduled visit, analysed as repeated measures, were smaller than 1 with a wide range of 95% CIs, except for Week 2. These results were consistent with the primary endpoint analysis.

In the sub-group analyses, no difference was observed between two groups for either previous exposure to anti-TNFa agents or concomitant use of oral corticosteroid.

No notable differences were observed in median serum CRP [12.750 and 11.750 mg/L in the placebo and amiselimod treatment groups, respectively] and median faecal calprotectin values [1455.0 and 1360.5 mg/kg, for placebo and amiselimod, respectively] at baseline. For CRP, there was no apparent trend seen in either of the two groups over the 14-week Treatment Period[s] [Supplementary Data 4, available at ECCO-JCC online]. The proportion of participants who showed CRP values of <5 mg/L was generally higher in the amiselimod 0.4-mg group than in the placebo group at all post-dose time points until Visit 7 [Week 14]. However, these data should be interpreted with caution because more participants in the amiselimod group discontinued due to worsening CD over time.

For median faecal calprotectin, there was a slightly numerically larger reduction in the amiselimod group [–106.0 mg/kg] compared with placebo [–61 mg/kg] at Visit 6 [Week 12] [Supplementary Data 4]. However, this difference may not be clinically meaningful as median values in both groups were far above the upper limit of normal [250 μg/g].

3.4. Pharmacokinetic and pharmacodynamic evaluations

Mean plasma concentrations for amiselimod and amiselimod-P increased during the Treatment Period to Visit 5 [Week 8], at which time point a steady state was achieved [Week 8]. The highest mean plasma trough concentration of amiselimod was achieved at Visit 6 [Week 12; 3.655 ng/mL]. However, approximately 90% of the highest mean plasma trough concentration had already been reached at Week 8 [3.287 ng/mL].

At baseline, the mean [SD] observed lymphocyte counts were similar across both treatment groups (1.757 [0.785] and 1.768 [0.801] × 10⁹/L for the placebo and amiselimod groups, respectively). Mean lymphocyte counts in the amiselimod group decreased over time, which confirmed the mode of action of amiselimod in the CD population.

Mean percentage changes from baseline in lymphocyte counts in the amiselimod group were 57.9% (Visit 3 [Week 2]), 47.7% (Visit 4 [Week 4]), 43.9% (Visit 5 [Week 8]), 46.0% (Visit 6 [Week 12]), and 41.8% (Visit 7 [Week 14]) [Figure 6].

Lymphocyte count reduction following amiselimod 0.4-mg dosing observed in this study was smaller than that observed in another clinical trial in patients with MS, in which approximately 70% of the lymphocyte count reduction from baseline was predicted at the steady state of multiple dosing with amiselimod 0.4 mg.^14,15

Pharmacokinetic and pharmacodynamic effects were investigated by disease location to assess the impact on drug absorption. The numbers of the participants with ileal disease only or colonic disease only were limited; however, the ileum-only group showed approximately 30% lower mean trough concentration compared with the colon-only group throughout treatment. Therefore, it could be hypothesised that lesions in small intestine might have disturbed drug absorption.

3.5. Safety evaluations

Overall, there were 47 participants [61.0%] with at least one treatment-emergent adverse event [TEAE] (21 participants [55.3%] and 26 participants [66.7%] in the placebo and amiselimod 0.4-mg groups, respectively) [Table 3].

No deaths were reported during this study. Overall, similar incidences of TEAEs, adverse drug reactions, and serious adverse reactions were observed in the amiselimod group and the placebo group, with the exception of the incidences of serious adverse events [SAEs] and SAEs that led to discontinuation, which were higher in the amiselimod group. The most frequently reported AEs were headache [13.0%], CD [9.1%], nasopharyngitis, and arthralgia [both 6.5%]. There were totals of seven participants with SAEs and four participants with SAEs leading to discontinuation of the investigational medicinal product in the amiselimod group. There were five CD-related SAEs, including one SAE of lymphopenia with a lymphocyte value of >0.20 × 10⁹/L. One participant reported SAEs of asthma and allergic dermatitis with a reasonable possibility of a relationship to amiselimod, and the participant was withdrawn due to another non-serious AE of drug hypersensitivity [Table 4].

There was a higher frequency of TEAEs with no reasonable possibility of a relationship to the study medication than TEAEs with a reasonable possibility (26 [33.8%] and 21 [27.3%] participants, respectively). Of the participants that reported TEAEs, the majority reported TEAEs that were mild or moderate([27 [35.1%] and 16 [20.8%] participants, respectively rather than severe (four participants [5.2%]).

A small increase in mean values of liver enzymes [i.e., ALT, AST, and GGT] and a small decrease in mean values of ANC were observed in the amiselimod group. However, those four laboratory parameters remained within the reference range over an entire treatment period and thus the findings were not considered to be clinically significant.

There were no consistent trends observed in any of 12-lead ECG parameters. There were no clinically relevant findings between the amiselimod and placebo groups in the mean hourly HR, and no clinically significant reports of bradycardia, atrioventricular block, and ventricular tachycardia in the amiselimod group.

Clinically significant macular oedema was reported in one participant on amiselimod at Week 14. Subsequently a TEAE of mild macular oedema was reported, and it was considered not resolved.

4. Discussion

In this prospective, placebo-controlled, randomised trial, we were unable to demonstrate efficacy of amiselimod 0.4 mg/day for 12 weeks in active CD. The population studied in this trial can be considered as representative of a typical CD patient population, similar to populations in other CD studies such as GEMINI-2 and UNITI.^16–18 Similarly, inflammatory biomarkers, namely CRP and faecal calprotectin, did not support a benefit of amiselimod in CD at the current dose.

A limitation of this analysis includes the fact that the sample size for this study could not be based on statistical power calculation because of lack of preliminary efficacy data. However, the number of participants was considered sufficient to provide initial evaluation of clinical efficacy and safety on the investigated population. The high placebo response rate [54.1% in CDAI 100 at Week 12] was one of the important findings which could have affected the result of this study. Endoscopic assessment is currently recognised as the most reliable objective measurement to ensure the presence of baseline disease activity; however, endoscopic assessment was not performed in this study, which may have potentially led to the high placebo response observed. We used the strategy that was taken in the GEMINI-2 trials, enrolling patients with ‘active’ CD reflected by biomarkers serum CRP and/or faecal calprotectin.¹⁶

In this study, disease activity was primarily measured using the CDAI. Use of the CDAI for CD clinical trials have been criticised for its lack of specificity. Thus, there was a possibility that CDAI score could not accurately reflect the changes of histopathological inflammations in the gut, although all currently approved CD treatments have been tested using the CDAI. Mean lymphocyte count, the PD parameter of amiselimod, decreased following dosing with amiselimod; but the magnitude of lymphocyte reduction was smaller than what was observed in another clinical trial with amiselimod in patients with MS. Therefore, the potential cause of the relatively weaker PD effect in CD patients was explored as post-hoc analyses. A possible reason may be that inflammation in the intestinal tract may have influenced drug absorption. Indeed, analysis of plasma concentrations by disease location showed that participants with ileal lesions only had lower drug concentrations compared with participants with colonic lesions only. Corresponding to the pharmacokinetic [PK] result, weaker PD effect in participants with ileum lesions only was observed. Based on those findings, there is a possibility that impaired drug absorption may have resulted in relatively lower PK and weaker PD effect in CD patients. In other words, this might suggest that higher doses and/or loading dose regimens of amiselimod could potentially be required in the setting of Crohn’s disease compared with other diseases showing proven efficacy of amiselimod, such as multiple sclerosis. It is reported that inflammatory macrophages are abnormally activated at the inflammation site in CD. Amiselimod has a potential effect of inhibiting the T cell-mediated inflammatory response. However, amiselimod does not reduce inflammatory macrophages at the site of inflammation, which might have contributed to the negative outcome of this study.^19–21

Treatment with amiselimod was generally well-tolerated and no new safety concerns for amiselimod were reported in CD patients. The majority of participants completed the 14-week treatment period. There were no serious adverse reactions of opportunistic infection, and no clinically significant bradycardia and arrhythmic episode in the amiselimod 0.4-mg group.

There were no clinically relevant findings between the amiselimod 0.4 mg and placebo groups in the mean hourly HR. Dissimilar to fingolimod, there seemed to be no scientific rationale or evidence to necessitate the 6-h cardiac safety monitoring for the initiation of amiselimod 0.4 mg treatment.

One AE of macular oedema was reported in the amiselimod treatment group for the first time, though it was reported as non-serious and improved after discontinuation of study drug administration. It has been reported that the S1P₁ receptor plays a pivotal role in the development of macular oedema among S1P receptor subtypes, and therefore all the S1P₁ receptor modulators have this potential risk as a class effect.⁹ In the case of fingolimod, the risk of macular oedema is considered to occur in a dose-dependent manner.²²

Since other S1P receptor modulators have been demonstrated for ulcerative colitis [currently a phase 2 study evaluating efficacy and safety of amiselimod in mild to moderate ulcerative colitis has been conducted],²³ further investigation for therapeutic effect of amiselimod in IBD is warranted.

In conclusion, this was the first placebo-controlled trial of an S1P modulator for the treatment of CD. Amiselimod 0.4 mg/day for 12 weeks was not superior to placebo for the induction of clinical response and remission. High placebo response rate and weaker lymphocyte reduction than observed in the MS clinical trial may have contributed to the negative efficacy result of this study. Treatment with amiselimod 0.4 mg was generally well tolerated, and no new safety concerns were reported in this study.

The data underlying this article cannot be shared since there is reasonable likelihood that patients’ anonymity cannot be maintained due to orphan disease, and there is also the limitation of participants’ informed consent.

Acknowledgements

Amiselimod Study Group: Czech Republic: S. Rejchrt, P. Svoboda, J. Ulbrych, M. Volfova, P. Vyhnalek, Z. Zadorova, T. Brabec, Z. Nemecek; France: B. Bonaz, J. L. Dupas, L. Peyrin-Biroulet, D. Larrey, J. M. Reimund; Germany: V. Aldinger, D. Baumgart, J. Hampe, J. Klaus, D. Benten, U. Seidler; Hungary: I. Fazekas, B. Nagy, L. Szegedi, Z. Tulassay; Israel: Y. Avni, S. Fishman, E. Goldin, D. Keret, E. Melzer, R. Safadi, M. Waterman; Italy: F. Rogai, G. Maconi, S. Danese, W. Fries, V. Savarino, S. Ardizzone, S. Marchi, G. C. Sturniolo, E. Villa, R. Pica; Japan: S. Motoya, T. Ashida, Y. Suzuki, S. Nakamura, T. Matsumoto, Y. Kakuta, M. Esaki, T. Matsui, A. Maemoto, O. Watanabe, T. Kanai, T. Kobayashi, K. Matsuda, M. Nagahori, K. Watanabe; The Netherlands: G. D’Haens, M. Pierik; Poland: A. Janke, D. Kleczkowski, A. Mamos, T. Arlukowicz; Slovakia: J. Baláź, I. Bunganic, M. Gregus, T. Hlavaty, F. Horvath, J. Usak, E. Veseliny, M. Batovsky; Ukraine: Y. Mostovoy, A. Dorofyeyev, N. Kharchenko, V. Vdovychenko, O. Golovchenko, V. Klymenko, O. Gyrina, M. Stanislavchuk, V. Pyrogovskyy. Study statistician: Pingping Ni, Mitsubishi Tanabe Pharma Europe, London, UK. Data Safety Monitoring Board members: Edouard Louis, DSMB Chair, Satish Keshav, and Etienne Aliot. Medical Writing Support, Clinical Operations Team, Sheikh Mohammed Ashfaq Rahman, Shiosaka Masashi, Yanai Yoshiari.

Funding

This study was sponsored by the Mitsubishi Tanabe Pharma Corporation. The sponsor participated in the design of the study, conduct of the study, data management, data analysis and interpretation and preparation, review, and approval of the manuscript.

Conflict of Interest

GRD’H has served as adviser for Abbvie, Ablynx, Allergan, Alphabiomics, Amakem, Amgen, AM Pharma, Applied Molecular Therapeutics; Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meyrs Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, DSM Pharma; Echo Pharmaceuticals, Eli Lilly, Engene, Exeliom Biosciences; Ferring, Dr Falk Pharma, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Gossamerbio, Hospira/Pfizer, Immunic, Johnson and Johnson, Kintai Therapeutics, Lycera, Medimetrics, Millenium/Takeda, Medtronics, Mitsubishi Tanabe Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer/Hospira, Photopill, Prodigest, Prometheus laboratories/Nestle, Progenity, Protagonist, RedHill; Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor; and received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor. SD reports consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ely Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor. MD is employed by Mitsubishi Tanabe Pharma Europe. TH has received lecture fees from Aspen Japan K.K, Abbvie GK, Ferring, Gilead Sciences, Janssen, JIMRO, Kisse Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku Pfizer, Takeda Pharmaceutical, and Zeria Pharmaceutical; advisory/consultancy fees from Abbvie, Bristol-Myers Squibb, Celltrion, EA Pharma, Eli Lilly, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceuticals, Pfizer, Takeda Pharmaceutical, Zeria Pharmaceutical; and research grants from Abbvie, EA Pharma, JIMRO, Otuska Holdings, and Zeria Pharmaceuticals. MW received lecture fees from Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical, Zeria Pharmaceutical, Astellas Pharma, Nippon Kayaku, Mochida Pharmaceutical, Pfizer Japan, Janssen Pharmaceutical K.K., Kissei Pharmaceutical, Celltrion Healthcare, Celgene K.K., Gilead Sciences; and consultancy fees from Takeda Pharmaceutical, AbbVie GK, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences; and research funding from Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical, Zeria Pharmaceutical, Astellas Pharma, MSD K.K., Daiichi Sankyo, Taiho Pharmaceutical, Nippon Kayaku, Mochida Pharmaceutical, Ayumi Pharmaceutical Corporation, Miyarisan Pharmaceutical, JIMRO, Asahi Kasei Medical, Kyorin Pharmaceutical, AbbVie GK, Kyowa Hakko Kirin, EA Pharma, Pfizer Japan, Kissei Pharmaceutical, Kaken Pharmaceutical, Alfresa Pharma Corporation, Toray Industries, Chugai Pharmaceutical, Gilead Sciences, and Fujirebio.

Author Contributions

All the authors had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of data analysis. All the authors contributed to the following: study concept and design, data acquisition, analysis and interpretation, revision of the manuscript for important intellectual content, statistical analysis, obtaining funding, and administrative/technical/material support. Drafting of the manuscript was carried out by the authors with the assistance of a medical writer [Brendan Thorne].

Presented at the annual ECCO congress, Vienna, February 2020.

References