A Study of the Safety and Efficacy of Golimumab in Subjects With Active Ankylosing Spondylitis

A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFalpha MonoclonalAntibody, Administered Subcutaneously, in Subjects With Active Ankylosing Spondylitis

The purpose of this study is to evaluate the safety and efficacy of subcutaneous injections (under the skin) of golimumab for the treatment of active ankylosing spondylitis [AS(arthritis of the spine)]. Efficacy will be measured by reduction in the signs and symptoms of active AS, including effects on back pain and stiffness, physical function, range of motion in the spine, quality of life, and rate of spine damage or fusion on x-ray.

Anti-tumor necrosis factor (TNF) agents have been shown to be effective treatment for patients with active ankylosing spondylitis (arthritis of the spine) who have not responded to conventional therapy. Golimumab is a new anti-TNFa agent. This is a multicenter, randomized (patients are assigned different treatments based on chance), double-blind (neither the patient nor the physician knows whether drug or placebo is being taken, or at what dosage), placebo-controlled, parallel group study comparing safety and efficacy of golimumab 50mg, golimumab 100mg, and placebo subcutaneous (under the skin) injections administered every 4 weeks, in patients with active AS. The total duration of treatment is approximately 5 years. In the first portion of the study, some patients will be randomly assigned to receive placebo treatment through the Week 20 injection; others will be assigned to golimumab 50mg or golimumab 100mg groups through the Week 20 injection. There is an "early escape" at Week 16 in the study whereby patients who meet criteria for having little improvement in their AS symptoms will be switched to golimumab if they were on placebo, or have the golimumab dose increased if they were originally assigned to the golimumab 50mg group. At Week 24, the placebo group patients will switch to golimumab 50mg injections, and all patients will continue receiving in a blinded manner either 50 or 100mg golimumab injections every 4 weeks until the first 104 weeks of data are fully collected on all the patients (database lock). After this 104-week database lock, everyone will be unblinded to the golimumab dose, and continue to receive golimumab treatment through Week 252 as part of a long-term extension phase of the study, with options for adjusting concomitant AS medications and/or increasing the dose of golimumab. The study hypothesis is that golimumab will be more effective than placebo in treating the signs and symptoms of AS, as measured by the ASsessment in Ankylosing Spondlitis (ASAS) 20 response criteria . Golimumab 50mg, Golimumab 100mg, or placebo injected under the skin every 4 weeks at Weeks 0, 4, 8, 12, 16, and 20, followed by injections of either Golimumab 50mg or Golimumab 100mg every 4 weeks for approximately 5 years total duration from the time of the first study agent injection.

Golimumab (CNTO 148); placebo SC injections every 4 wks thru wk 20 (unless early escape at wk 16);golimumab - if early escape, 50mg sc inj every 4wks from wk 16 up to 5yrs ;golimumab -50mg sc injection beginning wk 24 up to 5 yrs (unless early escape); golimumab- Dr's discretion after unblinding, dose adjust from 50 to 100mg

golimumab 50 mg sc injs every 4wks from wk 0 thru 5yrs (unless early escape at wk 16); golimumab - If early escape, 100mg sc injections every 4 wks beginning wk 16 up to 5 yrs ; golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100mg

SC injections every 4 wks thru wk 20 (unless early escape at wk 16);golimumab - if early escape, 50mg sc inj every 4wks from wk 16 up to 5yrs ;golimumab -50mg sc injection beginning wk 24 up to 5 yrs (unless early escape); golimumab- Dr's discretion after unblinding, dose adjust from 50 to 100mg

50 mg sc injs every 4wks from wk 0 thru 5yrs (unless early escape at wk 16); golimumab - If early escape, 100mg sc injections every 4 wks beginning wk 16 up to 5 yrs ; golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100mg

Number of patients who achieved a 20% improvement and at least 1 absolute improvement on a 0 to 10 cm scale from baseline to Week 14 in at least 3 of the 4 domains: patient global, total back pain, function or inflammation.

Number of patients who achieved a 20% improvement and at least 1 absolute improvement on a 0 to 10 cm scale from baseline to Week 24 at least 3 of the 4 domains: patient global, total back pain, function or inflammation.

The Bath Ankylosing Spondylitis Functional Index (BASFI) is calculated as the mean of 10 VAS, each of length 0 to 10 cm. Eight of the scales relate to functional capacity of patients while the other 2 relate to a patient's ability to cope with everyday life. Change from baseline is Wk 14 value minus baseline value.

The Bath Ankylosing Spondylitis Metrology Index (BASMI) is the sum of scores comprised of 5 measures (0=mild, 1=moderate & 2=severe): Tragus-to-wall; Lumbar flexion; Cervical rotation; Lumbar side flexion; Intermalleolar distance. BASMI ranges from 0 to 10. Change from baseline is Wk 14 value minus baseline value.

Inclusion Criteria: Diagnosis of "Definite AS" (arthritis of the spine) as defined by the modified New York criteria, for at least 3 months prior to first dose of study drug Symptoms of active disease at screening and at baseline visits, as evidenced by both a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of >= 4, and a Total Back Pain score of >= 4 (each on a scale of 0 to 10cm) Inadequate response to 3 months of continuous therapy with maximal recommended doses of NSAIDs, or else unable to receive a full 3 months of maximal NSAID therapy because of intolerance, toxicity, or contraindications to non-steroidal anti-inflammatory drugs (NSAIDs) Stable doses of methotrexate, sulfasalazine, hydroxychloroquine, low-dose corticosteroids, and NSAIDs are permitted. Exclusion Criteria: Patients cannot have complete ankylosis of the spine No prior treatment with biologic anti-TNF agents (infliximab, etanercept, adalimumab)

Leu JH, Adedokun OJ, Gargano C, Hsia EC, Xu Z, Shankar G. Immunogenicity of golimumab and its clinical relevance in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Rheumatology (Oxford). 2019 Mar 1;58(3):441-446. doi: 10.1093/rheumatology/key309.

Inman RD, Baraliakos X, Hermann KA, Braun J, Deodhar A, van der Heijde D, Xu S, Hsu B. Serum biomarkers and changes in clinical/MRI evidence of golimumab-treated patients with ankylosing spondylitis: results of the randomized, placebo-controlled GO-RAISE study. Arthritis Res Ther. 2016 Dec 28;18(1):304. doi: 10.1186/s13075-016-1200-1.

Kay J, Fleischmann R, Keystone E, Hsia EC, Hsu B, Zhou Y, Goldstein N, Braun J. Five-year Safety Data from 5 Clinical Trials of Subcutaneous Golimumab in Patients with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis. J Rheumatol. 2016 Dec;43(12):2120-2130. doi: 10.3899/jrheum.160420. Epub 2016 Nov 1.

Braun J, Baraliakos X, Hermann KG, Xu S, Hsu B. Serum C-reactive Protein Levels Demonstrate Predictive Value for Radiographic and Magnetic Resonance Imaging Outcomes in Patients with Active Ankylosing Spondylitis Treated with Golimumab. J Rheumatol. 2016 Sep;43(9):1704-12. doi: 10.3899/jrheum.160003. Epub 2016 Jul 15.

Braun J, Baraliakos X, Hermann KG, Xu S, Hsu B. Serum Vascular Endothelial Growth Factor Levels Lack Predictive Value in Patients with Active Ankylosing Spondylitis Treated with Golimumab. J Rheumatol. 2016 May;43(5):901-6. doi: 10.3899/jrheum.150897. Epub 2016 Mar 1.

Deodhar A, Braun J, Inman RD, van der Heijde D, Zhou Y, Xu S, Han C, Hsu B. Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 5-year results of the GO-RAISE study. Ann Rheum Dis. 2015 Apr;74(4):757-61. doi: 10.1136/annrheumdis-2014-205862. Epub 2014 Nov 11.

van der Heijde D, Braun J, Deodhar A, Inman RD, Xu S, Mack ME, Hsu B. Comparison of three enthesitis indices in a multicentre, randomized, placebo-controlled trial of golimumab in ankylosing spondylitis (GO-RAISE). Rheumatology (Oxford). 2013 Feb;52(2):321-5. doi: 10.1093/rheumatology/kes251. Epub 2012 Sep 28.

van der Heijde D, Deodhar A, Inman RD, Braun J, Hsu B, Mack M. Comparison of three methods for calculating the Bath Ankylosing Spondylitis Metrology Index in a randomized placebo-controlled study. Arthritis Care Res (Hoboken). 2012 Dec;64(12):1919-22. doi: 10.1002/acr.21771.

Deodhar A, Braun J, Inman RD, Mack M, Parasuraman S, Buchanan J, Hsu B, Gathany T, van der Heijde D. Golimumab reduces sleep disturbance in patients with active ankylosing spondylitis: results from a randomized, placebo-controlled trial. Arthritis Care Res (Hoboken). 2010 Sep;62(9):1266-71. doi: 10.1002/acr.20233.