Spondylitis, Ankylosing
Conditions
Keywords
Spondylitis, subcutaneous injection, Bechterew's Disease, Spondyloarthritis, Spondyloarthropathy
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALgolimumab
100 mg sc injections every 4 wks from wk 0 up to 5 yrs
BIOLOGICALGolimumab (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
Sponsors
Schering-Plough
Centocor, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment in Ankylosing Spondylitis 20 Responders at Week 14 | Week 14 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment in Ankylosing Spondylitis 20 Responders at Week 24 | Week 24 | 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. |
| Summary of Change From Baseline in Bath Ankylosing Spondylitis Functional Index at Week 14 | From Baseline to Week 14 | 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. |
| Summary of Change From Baseline in Bath Ankylosing Spondylitis Metrology Index at Week 14 | From Baseline to Week 14 | 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. |
Countries
Belgium, Canada, Finland, France, Germany, Netherlands, South Korea, Taiwan, United States
Participant flow
Recruitment details
356 patients were randomly assigned to treatment groups at 42 sites (17 in North America, 16 in Europe and 9 in Asia). Consent was obtained from the first patient on 13 Dec 2005. The last patient completed the final visit of the 24-week reporting period on 15 May 2007. The last patient completed the final visit of the 5-year period on 17 Jan 2012.
Participants by arm
| Arm | Count |
|---|---|
| Group I: Placebo Placebo SC injections every 4 weeks (wks) from Week (Wk) 0 thru Wk 20 (unless early escape at Wk 16); golimumab - if early escape, 50 mg SC every 4 wks from Wk 16 up to 5 yrs; golimumab - 50 mg SC beginning Wk 24 up to 5 yrs (unless early escape); golimumab- Dr's discretion after unblinding, dose adjust from 50 to 100 mg. | 78 |
| Group II: Golimumab 50 mg Golimumab 50 mg SC injections every 4 wks from Wk 0 thru 5 yrs (unless early escape at Wk 16); golimumab - If early escape, 100 mg SC every 4 wks beginning Wk 16 up to 5 yrs; golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100 mg. | 138 |
| Group III: Golimumab 100 mg Golimumab 100 mg SC injections every 4 wks from Wk 0 up to 5 yrs. | 140 |
| Total | 356 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 13 | 15 |
| Overall Study | Lost to Follow-up | 3 | 4 | 4 |
| Overall Study | Other | 1 | 12 | 9 |
| Overall Study | Unsatisfactory therapeutic effect | 8 | 13 | 14 |
Baseline characteristics
| Characteristic | Group I: Placebo | Group II: Golimumab 50 mg | Group III: Golimumab 100 mg | Total |
|---|---|---|---|---|
| Age Continuous | 40.6 years STANDARD_DEVIATION 12.71 | 39.2 years STANDARD_DEVIATION 12.46 | 38.6 years STANDARD_DEVIATION 11.3 | 39.3 years STANDARD_DEVIATION 12.06 |
| Sex: Female, Male Female | 23 Participants | 36 Participants | 42 Participants | 101 Participants |
| Sex: Female, Male Male | 55 Participants | 102 Participants | 98 Participants | 255 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 147 / 158 | 113 / 118 | 76 / 77 |
| serious Total, serious adverse events | 27 / 158 | 26 / 118 | 19 / 77 |
Outcome results
Primary
Assessment in Ankylosing Spondylitis 20 Responders at Week 14
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.
Time frame: Week 14
Population: Intent to treat (ITT). Patients considered non-responder if used any pre-specified prohibited medications or discontinued subcutaneous (SC) study agent due to lack of efficacy. Missing ASAS components at Week 14 were imputed by Last Observation Carried Forward (LOCF) unless all ASAS components are missing in which case considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Assessment in Ankylosing Spondylitis 20 Responders at Week 14 | 17 Participants |
| Group II: Golimumab 50 mg | Assessment in Ankylosing Spondylitis 20 Responders at Week 14 | 82 Participants |
| Group III: Golimumab 100 mg | Assessment in Ankylosing Spondylitis 20 Responders at Week 14 | 84 Participants |
| Combined: Groups II & III | Assessment in Ankylosing Spondylitis 20 Responders at Week 14 | 166 Participants |
Comparison: Null hypothesis: No difference in ASAS 20 response comparing Groups I vs II and Groups I vs III. The sample size of 75 patients (pts) in placebo and 135 pts per active group will provide \>=99% power to detect a difference in ASAS 20 response between treatment groups at alpha=0.05, assuming 50% of pts with screening CRP\<1.5mg/dL, and the difference in ASAS 20 response of 10-27.5% in pts with screening CRP\<1.5mg/dL and 32.5-45% in pts with screening CRP\>=1.5mg/dL, between Groups I vs II or III.p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Assessment in Ankylosing Spondylitis 20 Responders at Week 24
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.
Time frame: Week 24
Population: ITT. Patients (pts) considered non-responder if used any pre-specified prohibited medications or discontinued SC study agent due to lack of efficacy. Missing ASAS components were imputed by LOCF unless all ASAS components are missing in which case considered non-responders. Wk 16 ASAS response was used for pts with change in study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Assessment in Ankylosing Spondylitis 20 Responders at Week 24 | 18 P a r t i c ip an t s |
| Group II: Golimumab 50 mg | Assessment in Ankylosing Spondylitis 20 Responders at Week 24 | 77 P a r t i c ip an t s |
| Group III: Golimumab 100 mg | Assessment in Ankylosing Spondylitis 20 Responders at Week 24 | 92 P a r t i c ip an t s |
| Combined: Groups II & III | Assessment in Ankylosing Spondylitis 20 Responders at Week 24 | 169 P a r t i c ip an t s |
Comparison: Null hypothesis: No difference in ASAS 20 response comparing Groups I vs. II and Groups I vs. III.p-value: <0.001Cochran-Mantel-Haenszel
Comparison: Null hypothesis: no difference in ASAS 20 response between Group II and Group I.p-value: <0.001Cochran-Mantel-Haenszel
Comparison: Null hypothesis: no difference in ASAS 20 response between Group III and Group I.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Summary of Change From Baseline in Bath Ankylosing Spondylitis Functional Index at Week 14
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.
Time frame: From Baseline to Week 14
Population: Intent to treat (ITT). Patients considered non-change from baseline in BASFI if used any pre-specified prohibited medications or discontinued SC study agent due to lack of efficacy. Missing value of change from baseline in BASFI at Week 14 was imputed by Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Placebo | Summary of Change From Baseline in Bath Ankylosing Spondylitis Functional Index at Week 14 | 0.095 Change from baseline in BASFI Index |
| Group II: Golimumab 50 mg | Summary of Change From Baseline in Bath Ankylosing Spondylitis Functional Index at Week 14 | -1.375 Change from baseline in BASFI Index |
| Group III: Golimumab 100 mg | Summary of Change From Baseline in Bath Ankylosing Spondylitis Functional Index at Week 14 | -1.495 Change from baseline in BASFI Index |
| Combined: Groups II & III | Summary of Change From Baseline in Bath Ankylosing Spondylitis Functional Index at Week 14 | -1.420 Change from baseline in BASFI Index |
Comparison: Null hypothesis: No difference in change from baseline in BASFI comparing Groups I vs. II and Groups I vs. III.p-value: <0.001ANOVA on van der Waerden normal scores
Comparison: Null hypothesis: no difference in BASFI between Group II and Group I.p-value: <0.001ANOVA on van der Waerden normal scores
Comparison: Null hypothesis: no difference in BASFI between Group III and Group I.p-value: <0.001ANOVA on van der Waerden normal scores
Secondary
Summary of Change From Baseline in Bath Ankylosing Spondylitis Metrology Index at Week 14
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.
Time frame: From Baseline to Week 14
Population: Intent to treat (ITT). Patients considered non-change from baseline in BASMI if used any pre-specified prohibited medications or discontinued SC study agent due to lack of efficacy. Missing value of change from baseline in BASMI at Week 14 was imputed by Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo | Summary of Change From Baseline in Bath Ankylosing Spondylitis Metrology Index at Week 14 | -0.28 Change from baseline in BASMI Index | Standard Deviation 1.015 |
| Group II: Golimumab 50 mg | Summary of Change From Baseline in Bath Ankylosing Spondylitis Metrology Index at Week 14 | -0.36 Change from baseline in BASMI Index | Standard Deviation 1.112 |
| Group III: Golimumab 100 mg | Summary of Change From Baseline in Bath Ankylosing Spondylitis Metrology Index at Week 14 | -0.49 Change from baseline in BASMI Index | Standard Deviation 1.296 |
| Combined: Groups II & III | Summary of Change From Baseline in Bath Ankylosing Spondylitis Metrology Index at Week 14 | -0.43 Change from baseline in BASMI Index | Standard Deviation 1.208 |
Comparison: Null hypothesis: No difference in change from baseline in BASMI comparing Groups I vs. II and Groups I vs. III.p-value: 0.288ANOVA on van der Waerden normal scores
Comparison: Null hypothesis: no difference in BASMI between Group II and Group I.p-value: 0.444ANOVA on van der Waerden normal scores
Comparison: Null hypothesis: no difference in BASMI between Group III and Group I.p-value: 0.247ANOVA on van der Waerden normal scores