Randomised clinical trial: a placebo-controlled study of intravenous golimumab induction therapy for ulcerative colitis

P Rutgeerts, B G Feagan, C W Marano, L Padgett, R Strauss, J Johanns, O J Adedokun, C Guzzo, H Zhang, J-F Colombel, W Reinisch, P R Gibson, W J Sandborn, PURSUIT-IV study group, P Rutgeerts, B G Feagan, C W Marano, L Padgett, R Strauss, J Johanns, O J Adedokun, C Guzzo, H Zhang, J-F Colombel, W Reinisch, P R Gibson, W J Sandborn, PURSUIT-IV study group

Abstract

Background: Tumour necrosis factor alpha (TNFα)-antagonism effectively treats ulcerative colitis (UC). The golimumab clinical programme evaluated subcutaneous (SC) and intravenous (IV) induction, and SC maintenance regimens, in TNFα-antagonist-naïve patients with moderate-to-severe active UC despite conventional treatment.

Aim: To evaluate dose-response relationship, select IV golimumab induction doses for continued development, and evaluate the safety and efficacy of selected doses.

Methods: Adults with Mayo scores of 6-12 and endoscopic subscores ≥2 were enrolled into this multicentre, randomised, double-blind, placebo-controlled, integrated Phase 2/3 dose-finding/dose-confirming study. In Phase 2, 176 patients were randomised (1:1:1:1) to a single IV infusion of placebo, 1-, 2- or 4-mg/kg golimumab. While Phase 2 data were analysed to select doses for continued development, 71 additional patients were randomised. Phase 3 enrolment stopped after 44 additional patients were randomised (1:1:1) to placebo, 2- or 4-mg/kg golimumab. Due to insufficient power for the Phase 3 primary endpoint analysis (clinical response at week 6), efficacy analyses are considered exploratory and include all randomised patients.

Results: No dose-response was observed in Phase 2; however, higher serum golimumab exposure was associated with greater proportions of patients achieving more favourable clinical outcomes, clinical response and greater improvement in Mayo scores compared with placebo-treated patients and those with lower serum concentrations. Among all randomised patients, numerically greater proportions were in clinical response at week 6 in the 2- and 4-mg/kg golimumab groups compared with placebo [44.0% (33/75) and 41.6% (32/77) vs. 30.1% (22/73)].

Conclusions: Efficacy with single-dose golimumab IV induction was lower than expected and less than observed in the SC induction study. No new safety findings were observed. ClinicalTrials.gov Number, NCT00488774.

© 2015 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Median serum golimumab concentration (μg/mL) through Week 6; all treated patients.

References

    1. Sandborn WJ, van Assche G, Reinisch W, et al Adalimumab induces and maintains clinical remission in patients with moderate‐to‐severe ulcerative colitis. Gastroenterology 2012; 142: 257–65.
    1. Rutgeerts P, Sandborn WJ, Feagan BG, et al Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462–76.
    1. SIMPONI® (Golimumab) Prescribing Information. Horsham, PA: Janssen Biotech Inc, 2013.
    1. Kay J, Matteson EL, Dasgupta B, et al Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double‐blind, placebo‐controlled, dose‐ranging study. Arthritis Rheum 2008; 58: 964–75.
    1. Keystone E, Genovese MC, Klareskog L, et al Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52‐week results of the GO‐FORWARD study. Ann Rheum Dis 2010; 69: 1129–35.
    1. Emery P, Fleischmann RM, Moreland LW, et al Golimumab, a human anti‐tumor necrosis factor α monoclonal antibody, injected subcutaneously every four weeks in methotrexate‐naïve patients with active rheumatoid arthritis: twenty‐four‐week results of a phase III, multicenter, randomized, double‐blind, placebo‐controlled study of golimumab before methotrexate as first‐line therapy for early‐onset rheumatoid arthritis. Arthritis Rheum 2009; 60: 2272–83.
    1. Smolen JS, Kay J, Doyle MK, et al ; for the GO‐AFTER study investigators . Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor a inhibitors (GO‐AFTER study): a multicentre, randomized, double‐blind, placebo‐controlled, phase III trial. Lancet 2009; 374: 210–21.
    1. Kremer J, Ritchlin C, Mendelsohn A, et al Golimumab, a new human anti‐tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: forty‐eight‐week efficacy and safety results of a phase III randomized, double‐blind, placebo‐controlled study. Arthritis Rheum 2010; 62: 917–28. Erratum in Arthritis Rheum. 2010;62:3130.
    1. Braun J, Deodhar A, Inman RD, et al Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 104‐week results of the GO‐RAISE study. Ann Rheum Dis 2012; 71: 661–7.
    1. Kavanaugh A, van der Heijde D, McInnes IB, et al Golimumab in psoriatic arthritis: one‐year clinical efficacy, radiographic, and safety results from a phase III, randomized, placebo‐controlled trial. Arthritis Rheum 2012; 64: 2504–17.
    1. Sandborn WJ, Feagan BG, Marano C, et al Subcutaneous golimumab induces clinical response and remission in patients with moderate‐to‐severe ulcerative colitis. Gastroenterology 2014; 146: 85–95.
    1. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5‐aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study. N Engl J Med 1987; 317: 1625–9.
    1. D'Haens G, Sandborn WJ, Feagan BG, et al A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007; 132: 763–86.
    1. Sandborn WJ, Feagan BG, Marano C, et al Subcutaneous golimumab maintains clinical response in patients with moderate‐to‐severe ulcerative colitis. Gastroenterology 2014; 146: 96–109.
    1. Irvine EJ, Feagan B, Rochon J, et al Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn's Relapse Prevention Trial Study Group. Gastroenterology 1994; 106: 287–96.
    1. Zhuang Y, Xu Z, Frederick B, et al Golimumab pharmacokinetics after repeated subcutaneous and intravenous administrations in patients with rheumatoid arthritis and the effect of concomitant methotrexate: an open‐label, randomized study. Clin Ther 2012; 34: 77–90.
    1. Zhou H, Jang H, Fleischmann RM, et al Pharmacokinetics and safety of golimumab, a fully human anti‐TNF‐alpha monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol 2007; 47: 383–96.
    1. Targan SR, Hanauer SB, van Deventer SJH, et al A short‐term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. N Engl J Med 1997; 337: 1029–35.
    1. Weinblatt ME, Bingham CO, Mendelsohn AM, et al Intravenous golimumab is effective in patients with active rheumatoid arthritis despite methotrexate therapy with responses as early as week 2: results of the phase 3, randomised, multicentre, double‐blind, placebo‐controlled GO‐FURTHER trial. Ann Rheum Dis 2013; 72: 381–9.
    1. Reinisch W, Sandborn WJ, Hommes DW, et al Adalimumab for the induction of clinical remission in moderately to severely active ulcerative colitis; results of a randomized controlled trial. Gut 2011; 160: 780–7.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅