Infliximab Plus Methotrexate for Psoriatic Arthritis
Infliximab Plus Methotrexate for Psoriatic Arthritis
Enrolled patients were 18 years or older, rheumatoid factor negative, and had psoriasis in combination with peripheral articular disease with at least one of the following four characteristics for 3 or more months before screening: distal interphalangeal joint involvement; polyarticular arthritis in the absence of rheumatoid nodules; arthritis mutilans; or asymmetric peripheral arthritis. Active disease was defined as the presence of five or more swollen joints, five or more tender joints and at least one of the following: erythrocyte sedimentation rate (ESR) 28 mm/h or greater; C-reactive protein (CRP) 15 mg/l or greater, or morning stiffness for 45 min or more. Patients were naive to methotrexate, infliximab and other biological agents, and those with known contraindications to methotrexate or infliximab were excluded from participation. Leflunomide and other disease-modifying antirheumatic drugs (DMARD) could not be used within 6 months or 12 weeks, respectively, before study screening. Tacrolimus and ciclosporin could not be used in the 4 weeks before screening. The use of non-steroidal anti-inflammatory drugs (NSAID) and oral steroids (maximum dose 10 mg/day of prednisone or equivalent) was allowed if the dose was stable within 4 weeks before screening and kept stable throughout the study. Patients could not be included if they had active or untreated latent tuberculosis, opportunistic or other uncontrolled infections, a history of lymphoproliferative disease or malignancy in the 5 years before screening, or any other significant and uncontrolled disorder. A tuberculin skin test and chest x-ray were performed during screening within 30 days of receiving a first infliximab infusion and/or dose of methotrexate.
The study was carried out according to the Declaration of Helsinki and conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines. The study protocol was approved by the ethics committee at each of the participating study sites. All patients provided written informed consent before participating in any study-related activities.
This was a phase IIIB, randomised, prospective, open-label study conducted in 25 centres in Europe, the Middle East, South Africa and Turkey. Subjects were randomly assigned to one of two treatment arms (1:1) to receive either infliximab 5 mg/kg infusions at weeks 0, 2, 6 and 14 plus methotrexate 15 mg/week, or methotrexate 15 mg/week alone. In both groups, methotrexate could be increased to 20 mg/week at week 6 if improvement of 20% in the American College of Rheumatology (ACR) response criteria (ACR20) was not achieved. Assessments were performed at weeks 2, 6 and 14. The final study visit was at week 16.
The primary efficacy endpoint was the proportion of subjects achieving an ACR20 response from baseline at week 16. Secondary efficacy endpoints included proportions of patients with ACR50 and ACR70 responses, 75% improvement in the psoriasis area and severity index (PASI) in subjects whose baseline PASI was 2.5 or greater, and European League Against Rheumatism (EULAR) response. All rheumatologists were trained to perform PASI scoring. Change from baseline was investigated for the individual ACR core domains (ie, physician and patient global assessment of disease activity, patient self-reports of pain and disability, and CRP), PASI and disease activity score in 28 joints (DAS28) scores, number of digits with dactylitis, Maastricht ankylosing spondylitis enthesitis score, fatigue (visual analogue scale), duration of morning stiffness, ESR and CRP. As measures of clinical remission/minimal disease activity (MDA), the following outcomes were reported at week 16: absence of swollen joints, tender joints, enthesitis and dactylitis; normal CRP; DAS28 remission (<2.6); PASI90 response; and published criteria for MDA. Axial disease was not assessed.
Safety assessments included adverse event (AE) reporting, changes in physical examination findings, clinical laboratory test results and vital signs at all visits. Investigators assessed AE severity and relationship to study treatment.
It was determined that a sample size of 216 (108 per treatment group) would allow detection of a 20% difference in the proportion of patients achieving an ACR20 response with 85% power. This assessment was made assuming the use of a χ test with a significance level of 0.05 and assuming a 50% response for infliximab plus methotrexate and a 30% response for methotrexate alone. To allow for dropouts (the anticipated dropout rate was 10%), up to 243 subjects were to be enrolled.
The intent-to-treat (ITT) population included all randomly assigned subjects who received at least one dose of study medication and had baseline as well as at least one post-baseline efficacy assessment. The efficacy-evaluable per-protocol (PP) population included all of the subjects who followed the protocol and had both baseline and week 16 efficacy data. Protocol violators were identified and the PP population decided before database lock based on a blinded review of the data. The ITT population was the primary population for the superiority analyses. As the rate of exclusion due to protocol violations exceeded 5% in each treatment group, a PP population was also analysed.
A χ test was used to compare the proportions of subjects achieving an ACR20 response at week 16. To limit bias and capture the difference in response between the infliximab plus methotrexate and methotrexate-alone groups, the study protocol specified that non-responders were patients: with missing ACR data; who withdrew due to lack of efficacy or loss of response; who received additional treatments or study medication doses outside the protocol; and who underwent surgical joint procedures. This method was chosen over non-responder imputation, which is criticised in the statistical literature for being biased and invalid even under highly restrictive assumptions about patterns of missingness, such as data that are missing completely at random.
However, for the purpose of comparison with other studies, the non-responder imputation statistics for ACR20 and PASI75 at week 16 plus MDA at each study visit are also provided here. These post-hoc analyses were requested during the journal peer-review process.
Change from baseline in the PASI score was compared between treatment groups using analysis of covariance with baseline values as the covariate. Similarly, change from baseline in DAS28 and all other secondary endpoints were compared using analysis of covariance with baseline values as the covariate, unless there were analysis methods more appropriate for the observed distribution. The difference in EULAR response between groups at each visit was assessed by testing between treatments in mean ridit scores.
The safety population included all subjects who took at least one study dose. No formal statistical testing was performed to compare the safety data between treatment groups.
Methods
Patient Population
Enrolled patients were 18 years or older, rheumatoid factor negative, and had psoriasis in combination with peripheral articular disease with at least one of the following four characteristics for 3 or more months before screening: distal interphalangeal joint involvement; polyarticular arthritis in the absence of rheumatoid nodules; arthritis mutilans; or asymmetric peripheral arthritis. Active disease was defined as the presence of five or more swollen joints, five or more tender joints and at least one of the following: erythrocyte sedimentation rate (ESR) 28 mm/h or greater; C-reactive protein (CRP) 15 mg/l or greater, or morning stiffness for 45 min or more. Patients were naive to methotrexate, infliximab and other biological agents, and those with known contraindications to methotrexate or infliximab were excluded from participation. Leflunomide and other disease-modifying antirheumatic drugs (DMARD) could not be used within 6 months or 12 weeks, respectively, before study screening. Tacrolimus and ciclosporin could not be used in the 4 weeks before screening. The use of non-steroidal anti-inflammatory drugs (NSAID) and oral steroids (maximum dose 10 mg/day of prednisone or equivalent) was allowed if the dose was stable within 4 weeks before screening and kept stable throughout the study. Patients could not be included if they had active or untreated latent tuberculosis, opportunistic or other uncontrolled infections, a history of lymphoproliferative disease or malignancy in the 5 years before screening, or any other significant and uncontrolled disorder. A tuberculin skin test and chest x-ray were performed during screening within 30 days of receiving a first infliximab infusion and/or dose of methotrexate.
The study was carried out according to the Declaration of Helsinki and conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines. The study protocol was approved by the ethics committee at each of the participating study sites. All patients provided written informed consent before participating in any study-related activities.
Study Design
This was a phase IIIB, randomised, prospective, open-label study conducted in 25 centres in Europe, the Middle East, South Africa and Turkey. Subjects were randomly assigned to one of two treatment arms (1:1) to receive either infliximab 5 mg/kg infusions at weeks 0, 2, 6 and 14 plus methotrexate 15 mg/week, or methotrexate 15 mg/week alone. In both groups, methotrexate could be increased to 20 mg/week at week 6 if improvement of 20% in the American College of Rheumatology (ACR) response criteria (ACR20) was not achieved. Assessments were performed at weeks 2, 6 and 14. The final study visit was at week 16.
Outcome Measures
The primary efficacy endpoint was the proportion of subjects achieving an ACR20 response from baseline at week 16. Secondary efficacy endpoints included proportions of patients with ACR50 and ACR70 responses, 75% improvement in the psoriasis area and severity index (PASI) in subjects whose baseline PASI was 2.5 or greater, and European League Against Rheumatism (EULAR) response. All rheumatologists were trained to perform PASI scoring. Change from baseline was investigated for the individual ACR core domains (ie, physician and patient global assessment of disease activity, patient self-reports of pain and disability, and CRP), PASI and disease activity score in 28 joints (DAS28) scores, number of digits with dactylitis, Maastricht ankylosing spondylitis enthesitis score, fatigue (visual analogue scale), duration of morning stiffness, ESR and CRP. As measures of clinical remission/minimal disease activity (MDA), the following outcomes were reported at week 16: absence of swollen joints, tender joints, enthesitis and dactylitis; normal CRP; DAS28 remission (<2.6); PASI90 response; and published criteria for MDA. Axial disease was not assessed.
Safety assessments included adverse event (AE) reporting, changes in physical examination findings, clinical laboratory test results and vital signs at all visits. Investigators assessed AE severity and relationship to study treatment.
Statistical Analysis
It was determined that a sample size of 216 (108 per treatment group) would allow detection of a 20% difference in the proportion of patients achieving an ACR20 response with 85% power. This assessment was made assuming the use of a χ test with a significance level of 0.05 and assuming a 50% response for infliximab plus methotrexate and a 30% response for methotrexate alone. To allow for dropouts (the anticipated dropout rate was 10%), up to 243 subjects were to be enrolled.
The intent-to-treat (ITT) population included all randomly assigned subjects who received at least one dose of study medication and had baseline as well as at least one post-baseline efficacy assessment. The efficacy-evaluable per-protocol (PP) population included all of the subjects who followed the protocol and had both baseline and week 16 efficacy data. Protocol violators were identified and the PP population decided before database lock based on a blinded review of the data. The ITT population was the primary population for the superiority analyses. As the rate of exclusion due to protocol violations exceeded 5% in each treatment group, a PP population was also analysed.
A χ test was used to compare the proportions of subjects achieving an ACR20 response at week 16. To limit bias and capture the difference in response between the infliximab plus methotrexate and methotrexate-alone groups, the study protocol specified that non-responders were patients: with missing ACR data; who withdrew due to lack of efficacy or loss of response; who received additional treatments or study medication doses outside the protocol; and who underwent surgical joint procedures. This method was chosen over non-responder imputation, which is criticised in the statistical literature for being biased and invalid even under highly restrictive assumptions about patterns of missingness, such as data that are missing completely at random.
However, for the purpose of comparison with other studies, the non-responder imputation statistics for ACR20 and PASI75 at week 16 plus MDA at each study visit are also provided here. These post-hoc analyses were requested during the journal peer-review process.
Change from baseline in the PASI score was compared between treatment groups using analysis of covariance with baseline values as the covariate. Similarly, change from baseline in DAS28 and all other secondary endpoints were compared using analysis of covariance with baseline values as the covariate, unless there were analysis methods more appropriate for the observed distribution. The difference in EULAR response between groups at each visit was assessed by testing between treatments in mean ridit scores.
The safety population included all subjects who took at least one study dose. No formal statistical testing was performed to compare the safety data between treatment groups.
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