Arthritis, Psoriatic
Conditions
Keywords
Psoriatic Arthritis, Spondyloarthritis, Spondyloarthropathy, subcutaneous injection
Brief summary
The purpose of this study is to evaluate the safety and efficacy (improvement of signs and symptoms) of subcutaneous (under the skin) injections of golimumab for the treatment of active psoriatic arthritis (PsA). Efficacy will be measured by reduction in the signs and symptoms of active PsA, including effects on joint pain and swelling, changes on x-ray related to joint damage, psoriasis skin lesions, physical function, and quality of life.
Detailed description
Anti-tumor necrosis factor (TNF) agents have been shown to be effective in improving arthritis and psoriasis symptoms in patients with active psoriatic arthritis. 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 injections administered every 4 weeks, in subjects with active PsA. 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 minimal improvement in their joints 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 subjects 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 52 weeks of data are fully collected on all the subjects (database lock). After this 52-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 PsA medications and/or increasing the dose of golimumab. The study hypothesis is that golimumab will be more effective than placebo both in terms of reducing the signs and symptoms of PsA, as measured by the American College of Rheumatology (ACR) 20 response at Week 14, and inhibiting the amount of damage due to PsA seen on x-rays of the hand and feet at Week 24, while maintaining an acceptable safety profile. 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
50 mg sc injs every 4 wks from wk 0 thru 5 yrs (unless early escape at wk 16); golimumab - if early escape, 100mg sc injection every 4 wks beginning wk 16 up to 5 yrs; golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100mg
BIOLOGICALPlacebo; golimumab
SC injections ever 4 wks thru Wk 20 (unless early escape at wk 16); golimumab - if early escape, 50mg sc injection from wk 16 up to 5 yrs; 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 100 mg
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
* Psoriatic arthritis (PsA) diagnosed \> 6months prior * Active PsA at the time of screening and at baseline visits, with \>= 3 swollen joints and \>= 3 tender joints * Have at least 1 of the PsA subsets (DIP joint arthritis, polyarticular arthritis without rheumatoid nodules, arthritis mutilans, asymmetric peripheral arthritis, or spondylitis with peripheral arthritis) * Active plaque psoriasis with a lesion \>= 2cm in diameter * Active arthritis despite current disease modifying anti-rheumatic drug (DMARD) or nonsteroidal anti-inflammatory drug (NSAID) therapy * Stable doses of methotrexate, low-dose corticosteroids, and NSAIDs are permitted.
Exclusion criteria
* No prior treatment with biologic anti-TNF agents (infliximab, etanercept, adalimumab) * No treatment with alefacept or efalizumab within 3 months prior to the first study drug injection * No DMARDs other than methotrexate, or immunosuppressive drugs within 4 weeks prior to the first study drug injection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| American College of Rheumatology (ACR) 20 Response at Week 14 | Baseline (Week 0), Week 4, Week 8 and Week 14 | ACR 20 response is an improvement of \>= 20% from baseline (baseline measurement is defined as the closest measurement taken prior to or at the time of the initiation of study medication administration) in both the tender and swollen joint count and in at least 3 of the 5 assessments (Patient's assessment of pain, Patient's global assessment of disease activity, Physician's global assessment of disease activity Visual Analogue Scale \[VAS\], Health Assessment Questionnaire \[HAQ\] and C-reactive protein \[CRP\]) |
| Change From Baseline in Total Radiographic Scores of the Hands and Feet at Week 24 | Baseline and Week 24 | Summary of change from baseline in total van der Heijde-Sharp (vdH-S) score of the hands and feet, as modified for psoriatic arthritis, at Week 24. The vdH-S score is the sum of joint erosion score and joint-space narrowing (JSN) score. The total score ranges from 0 to 528 with higher scores indicating more joint damage. For the change from baseline, positive values show an increase in damage. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Psoriasis Area and Severity Index (PASI) 75 Response at Week 14 in a Subset of Patients With ≥ 3 Percent Body Surface Area (BSA) Psoriasis Skin Involvement at Baseline | Baseline, Week 4, Week 8 and Week 14 | Number of patients (randomized patients with \>= 3 percent Body Surface Area \[BSA\] psoriasis skin involvement at baseline) with Psoriasis Area and Severity Index (PASI) 75 response at Week 14. PASI is the widely used tool for the measurement of severity of psoriasis. PASI combines the assessment of the severity of lesions and the area affected into a single score in the range of 0 to 72. Zero (0) means no disease and 72 means maximal disease. PASI 75 Response at Week 14 means reduction in PASI score by 75 percent at Week 14. |
| Improvement From Baseline in Health Assessment Questionnaire Scores at Week 24 | Baseline, Week 4, Week 8, Week 14, Week 16, Week 20 and Week 24 | Summary of improvement from baseline in Health Assessment Questionnaire (HAQ) score at Week (Wk) 24. This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area based on the worst score from the questions that pertain to that task. The HAQ score is determined by the average of the 8 scores. |
| Change From Baseline in the Physical Component Summary Score of the 36-item Short Form Health Survey at Week 14 | Baseline and Week 14 | The short form health survey (SF-36) is a well-validated and widely used quality-of-life instrument employed in numerous disease states. It is a self-administered survey that measures eight domains of health including: physical functioning, role limitations due to physical health (role-physical), bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems (role-emotional) and general mental health. Scoring of the SF-36 was based on the SF-36 Manual and Interpretation Guide. Worst value is 0 and best value is 100. |
| American College of Rheumatology 20 at Week 24 | Baseline, Week 4, Week 8, Week 14, Week 16, Week 20 and Week 24 | Number of Patients who achieved an American College of Rheumatology (ACR) 20 response at Week (Wk) 24. ACR 20 response is an improvement of \>= 20% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments (Patient's assessment of pain, Patient's global assessment of disease activity, Physician's global assessment of disease activity Visual Analogue Scale \[VAS\], Health Assessment Questionnaire \[HAQ\] and C-reactive protein \[CRP\]) |
Countries
Belgium, Canada, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
405 patients were randomized at 57 centers: 35 in North America (17 in the United States and 18 in Canada) and 22 in Europe (5 in Belgium, 10 in Poland, 3 in Spain, and 4 in the United Kingdom). The first patient was enrolled on 12 Dec 2005. The date of the last patient visit for the week (Wk) 24 reporting period was 14 May 2007.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Placebo Placebo subcutaneous (SC) injections every 4 weeks from week (Wk) 0 through Wk 20 (unless early escape at Wk 16); golimumab - if early escape, 50 mg SC injection from Wk 16 up to 5 years (yrs); golimumab - 50 mg SC injection beginning Wk 24 up to 5 yrs (unless early escape); golimumab - Doctor's (Dr's) discretion after unblinding (last patient completes the Wk 52 evaluation and database is locked), dose adjust from 50 to 100 mg. | 113 |
| Group 2: Golimumab 50 mg Golimumab 50 mg SC injections every 4 weeks from Wk 0 through 5 yrs (unless early escape at Wk 16); golimumab - if early escape, 100 mg SC injection every 4 weeks beginning Wk 16 up to 5 yrs; golimumab - Dr's discretion after unblinding (last patient completes the Wk 52 evaluation and database is locked), dose adjust from 50 to 100 mg. | 146 |
| Group 3: Golimumab 100 mg Golimumab 100 mg SC injections every 4 weeks from Wk 0 up to 5 yrs. | 146 |
| Total | 405 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 14 | 18 | 18 |
| Overall Study | Death | 0 | 1 | 2 |
| Overall Study | Lost to Follow-up | 2 | 5 | 3 |
| Overall Study | Other | 11 | 19 | 10 |
| Overall Study | Unsatisfactory therapeutic effect | 9 | 8 | 6 |
Baseline characteristics
| Characteristic | Group 1: Placebo | Group 2: Golimumab 50 mg | Group 3: Golimumab 100 mg | Total |
|---|---|---|---|---|
| Age Continuous | 47 years STANDARD_DEVIATION 10.56 | 45.7 years STANDARD_DEVIATION 10.7 | 48.2 years STANDARD_DEVIATION 10.93 | 47 years STANDARD_DEVIATION 10.77 |
| Sex: Female, Male Female | 44 Participants | 57 Participants | 60 Participants | 161 Participants |
| Sex: Female, Male Male | 69 Participants | 89 Participants | 86 Participants | 244 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 | 107 / 139 | 91 / 109 | 113 / 146 |
| serious Total, serious adverse events | 29 / 139 | 25 / 109 | 29 / 146 |
Outcome results
Primary
American College of Rheumatology (ACR) 20 Response at Week 14
ACR 20 response is an improvement of \>= 20% from baseline (baseline measurement is defined as the closest measurement taken prior to or at the time of the initiation of study medication administration) in both the tender and swollen joint count and in at least 3 of the 5 assessments (Patient's assessment of pain, Patient's global assessment of disease activity, Physician's global assessment of disease activity Visual Analogue Scale \[VAS\], Health Assessment Questionnaire \[HAQ\] and C-reactive protein \[CRP\])
Time frame: Baseline (Week 0), Week 4, Week 8 and Week 14
Population: Intention 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 ACR components at Week 14 were imputed by Last Observation Carried Forward (LOCF) unless all ACR components are missing in which case considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | American College of Rheumatology (ACR) 20 Response at Week 14 | 10 Participants |
| Group II: Golimumab 50 mg | American College of Rheumatology (ACR) 20 Response at Week 14 | 74 Participants |
| Group III: Golimumab 100 mg | American College of Rheumatology (ACR) 20 Response at Week 14 | 66 Participants |
| Combined: Group II & III | American College of Rheumatology (ACR) 20 Response at Week 14 | 140 Participants |
Comparison: Null Hypothesis: No difference in ACR 20 response comparing Groups I vs II and Groups I vs III. Sample size (n=396; 110 placebo, 286 combined golimumab) provided \>98% power to detect a significant difference (alpha=0.05) in ACR 20 response between treatment groups, assuming equal proportions of subjects receiving methotrexate (MTX) at baseline and the difference in ACR 20 response of 27% in subjects without MTX and 17-27% in subjects with MTX, between placebo and combined golimumab groups.p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
Primary
Change From Baseline in Total Radiographic Scores of the Hands and Feet at Week 24
Summary of change from baseline in total van der Heijde-Sharp (vdH-S) score of the hands and feet, as modified for psoriatic arthritis, at Week 24. The vdH-S score is the sum of joint erosion score and joint-space narrowing (JSN) score. The total score ranges from 0 to 528 with higher scores indicating more joint damage. For the change from baseline, positive values show an increase in damage.
Time frame: Baseline and Week 24
Population: Intent-to-treat analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo | Change From Baseline in Total Radiographic Scores of the Hands and Feet at Week 24 | 0.27 Scores on a scale | Standard Deviation 1.259 |
| Group II: Golimumab 50 mg | Change From Baseline in Total Radiographic Scores of the Hands and Feet at Week 24 | -0.16 Scores on a scale | Standard Deviation 1.309 |
| Group III: Golimumab 100 mg | Change From Baseline in Total Radiographic Scores of the Hands and Feet at Week 24 | -0.02 Scores on a scale | Standard Deviation 1.322 |
| Combined: Group II & III | Change From Baseline in Total Radiographic Scores of the Hands and Feet at Week 24 | -0.09 Scores on a scale | Standard Deviation 1.315 |
Comparison: Null Hypothesis: There is no difference in change from baseline among 3 treatment groups. Sample size (n=396, 110 placebo, 286 combined golimumab) provided \>93% power to detect a significant difference (alpha=0.05) in change from baseline between treatment groups, assuming 50% of subjects received MTX at baseline, and mean change from baseline for combined golimumab of 0, and a mean increase for placebo of 0.1 in subjects who received MTX at baseline and 0.6 in subjects who did not receive MTXp-value: 0.015ANOVA
p-value: 0.011ANOVA
p-value: 0.086ANOVA
Secondary
American College of Rheumatology 20 at Week 24
Number of Patients who achieved an American College of Rheumatology (ACR) 20 response at Week (Wk) 24. ACR 20 response is an improvement of \>= 20% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments (Patient's assessment of pain, Patient's global assessment of disease activity, Physician's global assessment of disease activity Visual Analogue Scale \[VAS\], Health Assessment Questionnaire \[HAQ\] and C-reactive protein \[CRP\])
Time frame: Baseline, Week 4, Week 8, Week 14, Week 16, Week 20 and Week 24
Population: ITT. Patients considered non-responder if used any pre-specified prohibited medications or discontinued SC study agent due to lack of efficacy. Missing ACR components were imputed by LOCF unless all ACR components are missing in which case considered non-responders. Wk 16 ACR response was used for patients with change in study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | American College of Rheumatology 20 at Week 24 | 14 P a r t i c ip an t s |
| Group II: Golimumab 50 mg | American College of Rheumatology 20 at Week 24 | 76 P a r t i c ip an t s |
| Group III: Golimumab 100 mg | American College of Rheumatology 20 at Week 24 | 89 P a r t i c ip an t s |
| Combined: Group II & III | American College of Rheumatology 20 at Week 24 | 165 P a r t i c ip an t s |
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Change From Baseline in the Physical Component Summary Score of the 36-item Short Form Health Survey at Week 14
The short form health survey (SF-36) is a well-validated and widely used quality-of-life instrument employed in numerous disease states. It is a self-administered survey that measures eight domains of health including: physical functioning, role limitations due to physical health (role-physical), bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems (role-emotional) and general mental health. Scoring of the SF-36 was based on the SF-36 Manual and Interpretation Guide. Worst value is 0 and best value is 100.
Time frame: Baseline and Week 14
Population: Intention to treat (ITT). Missing scores were imputed by Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo | Change From Baseline in the Physical Component Summary Score of the 36-item Short Form Health Survey at Week 14 | 0.63 scores on a scale | Standard Deviation 7.676 |
| Group II: Golimumab 50 mg | Change From Baseline in the Physical Component Summary Score of the 36-item Short Form Health Survey at Week 14 | 6.53 scores on a scale | Standard Deviation 8.882 |
| Group III: Golimumab 100 mg | Change From Baseline in the Physical Component Summary Score of the 36-item Short Form Health Survey at Week 14 | 7.85 scores on a scale | Standard Deviation 9.547 |
| Combined: Group II & III | Change From Baseline in the Physical Component Summary Score of the 36-item Short Form Health Survey at Week 14 | 7.19 scores on a scale | Standard Deviation 9.229 |
p-value: <0.001ANOVA on van der Waerden normal scores
p-value: <0.001ANOVA on van der Waerden normal scores
p-value: <0.001ANOVA on van der Waerden normal scores
Secondary
Improvement From Baseline in Health Assessment Questionnaire Scores at Week 24
Summary of improvement from baseline in Health Assessment Questionnaire (HAQ) score at Week (Wk) 24. This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area based on the worst score from the questions that pertain to that task. The HAQ score is determined by the average of the 8 scores.
Time frame: Baseline, Week 4, Week 8, Week 14, Week 16, Week 20 and Week 24
Population: Intention to treat (ITT). Missing scores were imputed by LOCF. Week (Wk) 16 scores were used for patients with change in study treatment. Week 16 HAQ scores were used for patients with change in study treatment.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo | Improvement From Baseline in Health Assessment Questionnaire Scores at Week 24 | 0.0000 scores on a scale | Inter-Quartile Range 0.48796 |
| Group II: Golimumab 50 mg | Improvement From Baseline in Health Assessment Questionnaire Scores at Week 24 | 0.2500 scores on a scale | Inter-Quartile Range 0.55215 |
| Group III: Golimumab 100 mg | Improvement From Baseline in Health Assessment Questionnaire Scores at Week 24 | 0.3750 scores on a scale | Inter-Quartile Range 0.50329 |
| Combined: Group II & III | Improvement From Baseline in Health Assessment Questionnaire Scores at Week 24 | 0.2500 scores on a scale | Inter-Quartile Range 0.52811 |
p-value: <0.001ANOVA on van der Waerden normal scores
p-value: <0.001ANOVA on van der Waerden normal scores
p-value: <0.001ANOVA on van der Waerden normal scores
Secondary
Psoriasis Area and Severity Index (PASI) 75 Response at Week 14 in a Subset of Patients With ≥ 3 Percent Body Surface Area (BSA) Psoriasis Skin Involvement at Baseline
Number of patients (randomized patients with \>= 3 percent Body Surface Area \[BSA\] psoriasis skin involvement at baseline) with Psoriasis Area and Severity Index (PASI) 75 response at Week 14. PASI is the widely used tool for the measurement of severity of psoriasis. PASI combines the assessment of the severity of lesions and the area affected into a single score in the range of 0 to 72. Zero (0) means no disease and 72 means maximal disease. PASI 75 Response at Week 14 means reduction in PASI score by 75 percent at Week 14.
Time frame: Baseline, Week 4, Week 8 and Week 14
Population: In a subset of patients with ≥ 3 percent body surface area (BSA) psoriasis skin involvement at baseline. Missing scores were imputed by Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Psoriasis Area and Severity Index (PASI) 75 Response at Week 14 in a Subset of Patients With ≥ 3 Percent Body Surface Area (BSA) Psoriasis Skin Involvement at Baseline | 2 Participants |
| Group II: Golimumab 50 mg | Psoriasis Area and Severity Index (PASI) 75 Response at Week 14 in a Subset of Patients With ≥ 3 Percent Body Surface Area (BSA) Psoriasis Skin Involvement at Baseline | 44 Participants |
| Group III: Golimumab 100 mg | Psoriasis Area and Severity Index (PASI) 75 Response at Week 14 in a Subset of Patients With ≥ 3 Percent Body Surface Area (BSA) Psoriasis Skin Involvement at Baseline | 63 Participants |
| Combined: Group II & III | Psoriasis Area and Severity Index (PASI) 75 Response at Week 14 in a Subset of Patients With ≥ 3 Percent Body Surface Area (BSA) Psoriasis Skin Involvement at Baseline | 107 Participants |
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel