A Study to Evaluate the NSAIDS Sparing Effect of Etanercept in Subjects With Axial Spondyloarthritis

Study Overview
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Brief Summary
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This study will compare the Non Steroidal Anti-Inflammatory Drugs (NSAIDs) sparing effect of etanercept with that of placebo in adult subjects with axial Spondyloarthritis.

Official Title
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A Multi Centre, Double Blind, Placebo-controlled Study to Evaluate the Non Steroidal Anti-inflamatory Drugs (NSAIDS) Sparing Effect of Etanercept in Adult Subjects With Axial Involvement of Spondyloarthritis

Conditions
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Axial Spondyloarthritis

Intervention / Treatment
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* Drug: etanercept
* Drug: etanercept
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects aged 18 years and over at the time of consent to the study. Diagnosis of SpA, as defined by the ASAS criteria for axial SpA Axial involvement refractory to previous or current intake of NSAIDs, defined as at least 2 NSAIDs at maximum tolerated dose determined from past medical history taken for a duration of > 1 month (for both NSAIDs combined) before the Screening visit. Active axial involvement defined by mini BASDAI Exclusion Criteria: Subjects who are investigational site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial. Subjects who have received any previous treatment with etanercept or other TNFα inhibitors or biologic agents. Subjects with a known or expected allergy, contraindication, or hypersensitivity to etanercept or its excipients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: etanercept<br>Group A: etanercept 50 mg subcutaneous (SC) injections once weekly for 16 weeks. | Drug: etanercept<br>* etanercept 50 mg subcutaneous (SC) injections once weekly for 16 weeks.<br>* Other names: Enbrel;|
| Placebo Comparator: etanercept-placebo<br>Group B: placebo subcutaneous (SC) injections once weekly for (how many) weeks follwed by etanercept 50 mg SC injections once weekly. | Drug: etanercept<br>* etanercept 50 mg subcutaneous (SC) injections once weekly for 8 weeks following the prior 8 weeks of placebo.<br>* Other names: Enbrel;Drug: placebo<br>* placebo subcutaneous (SC) injections once weekly for 8 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Non Steroidal Anti Inflammatory Drug (NSAID) Assessment of the SpondyloArthritis International Society (ASAS) Score at Week 8. | Diary data from the 7 days prior to respective visit were used to evaluate the endpoint, where the score was only calculated if at least 5 of the 7 days data were available. Score was calculated from NSAID usage completed on diary cards considering NSAID type, total daily dose and number of days consumed. The Daily diclofenac-equivalent dose score was derived by converting each daily dose of NSAID to a percentage dose equivalent of 150 mg diclofenac; e.g. 1000 mg naproxen is equivalent to 150 mg diclofenac. For each NSAID, the percentage diclofenac-equivalent score is then multiplied by daily dose frequency and proportion of the period where dose was taken. Ie Score=M x F x n/N (M: Percentage dose equivalent to diclofenac; F=Daily Dose Frequency; n=number of days with NSAID; N=number of days in period). The NSAID ASAS score is the sum of all such scores for all NSAIDs taken during the period. The minimum value is 0 and a higher NSAID-ASAS value indicates greater NSAIDs consumption. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total NSAID ASAS [Area Under Curve (AUC)] Score From Baseline to Week 8. | The total NSAID score for the first 8 weeks of randomized treatment was calculated as an AUC using the linear trapezoidal rule. LOCF will only be applied where the subject is still in the study and the NSAID score is missing. | Week 8 | 
| Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 4. | A numeric rating scale was used, for questions 1-5 (Fatigue, Spinal Pain, Joint pain or Swelling, Discomfort and Morning stiffness severity respectively) on a scale from 0 (none) to 10 (very severe). Question 6 (morning stiffness duration) was recorded on a scale of 0 (0 or more hours) to 10 (2 hours). To give the five major Ankylosing Spondylitis (AS) symptoms equal weighting, the average of the two scores relating to morning stiffness was taken. This averaged morning stiffness score was then summed with the remaining 4 questions, resulting in a composite score on a scale of 0-50, which was then divided by 5 to give the final BASDAI score on a scale of 0-10. | Week 4 | 
| Change From Baseline in BASDAI at Week 8 | A numeric rating scale was used, for questions 1-5 (Fatigue, Spinal Pain, Joint pain or Swelling, Discomfort and Morning stiffness severity respectively) on a scale from 0 (none) to 10 (very severe). Question 6 (morning stiffness duration) was recorded on a scale of 0 (0 or more hours) to 10 (2 hours). To give the five major AS symptoms equal weighting, the average of the two scores relating to morning stiffness was taken. This averaged morning stiffness score was then summed with the remaining 4 questions, resulting in a composite score on a scale of 0-50, which was then divided by 5 to give the final BASDAI score on a scale of 0-10. | Week 8 | 
| Change From Baseline in BASDAI Score at Weeks 12 and 16. | A numeric rating scale was used, for questions 1-5 (Fatigue, Spinal Pain, Joint pain or Swelling, Discomfort and Morning stiffness severity respectively) on a scale from 0 (none) to 10 (very severe). Question 6 (morning stiffness duration) was recorded on a scale of 0 (0 or more hours) to 10 (2 hours). To give the five major AS symptoms equal weighting, the average of the two scores relating to morning stiffness was taken. This averaged morning stiffness score was then summed with the remaining 4 questions, resulting in a composite score on a scale of 0-50, which was then divided by 5 to give the final BASDAI score on a scale of 0-10. | Week 12 and 16 | 
| Number of Participants Using NSAIDs at Week 8. | Participants who received NSAIDs at Week 8 were reported. | Week 8 | 
| Change From Baseline in Mini BASDAI at Week 8 (AUC). | A numeric rating scale was used, for questions 1-5 (Fatigue, Spinal Pain, Joint pain or Swelling, Discomfort and Morning stiffness severity respectively) on a scale from 0 (none) to 10 (very severe). Question 6 (morning stiffness duration) was recorded on a scale of 0 (0 or more hours) to 10 (2 hours). To give the five major AS symptoms equal weighting, the average of the two scores relating to morning stiffness was taken. This averaged morning stiffness score was then summed with the remaining 4 questions, resulting in a composite score on a scale of 0-50, which was then divided by 5 to give the final BASDAI score on a scale of 0-10. | Week 8 | 
| Number of Participants Achieved BASDAI 50 at Week 8. | Response was defined as a 50% improvement of the baseline BASDAI after 8 Weeks. | Week 8 | 
| Number of Participants Achieved BASDAI 50 at Weeks 4, 12 and 16. | Response was defined as a 50% improvement of the baseline BASDAI after 4, 12 and 16 Weeks. | Weeks 4, 12 and 16 | 
| Number of Participants Achieving ASAS 20 (Assessment of the Spondylo Arthritis International Society 20) at Weeks 4, 12 and 16 | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 20 = 20% improvement from baseline and an absolute change ≥ 10 units on a 0-100 scale (0=no disease activity; 100=high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Weeks 4, 12 and 16 | 
| Number of Participants Achieving ASAS 20 at Week 8 | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 20 = 20% improvement from baseline and an absolute change ≥ 10 units on a 0-100 scale (0=no disease activity; 100=high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Week 8 | 
| Number of Participants Achieving ASAS 40 at Weeks 4, 12 and 16. | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 40 = 40% improvement from baseline and an absolute change ≥ 20 units on a 0-100 scale (0=no disease activity, 100=high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Weeks 4, 12 and 16 | 
| Number of Participants Achieving ASAS 40 at Week 8 | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 40 = 40% improvement from baseline and an absolute change ≥ 20 units on a 0-100 scale (0=no disease activity, 100=high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Week 8 | 
| Number of Participants Achieving ASAS 70 at Weeks 4, 12 and 16. | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 70 = 70% improvement from baseline and an absolute change ≥ 20 units on a 0-100 scale (0=no disease activity, 100=high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Weeks 4, 12 and 16 | 
| Number of Participants Achieving ASAS 70 at Week 8 | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 70 = 70% improvement from baseline and an absolute change ≥ 20 units on a 0-100 scale (0=no disease activity, 100=high disease activity) | Week 8 | 
| Change From Baseline in ASDAS CRP (Ankylosing Spondylitis Disease Activity Score-C Reactive Protein) Score at Week 4. | The ASDAS-CRP was derived from back pain, duration of morning stiffness, patient global score and peripheral pain/swelling. The scores were categorized as follows : inactive disease(< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity ( > 3.5). ASDAS CRP is calculated as follows: ASDAS CRP=0.12*Total Back Pain+0.06*Duration of Morning Stiffness+0.11*Patient Global+0.07*Peripheral Pain/Swelling+0.58*ln(CRP+1). | Week 4 | 
| Change From Baseline in ASDAS CRP Score at Week 8. | The ASDAS-CRP was derived from back pain, duration of morning stiffness, patient global score and peripheral pain/swelling. The scores were categorized as follows : inactive disease(< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity ( > 3.5). ASDAS CRP is calculated as follows: ASDAS CRP=0.12*Total Back Pain+0.06*Duration of Morning Stiffness+0.11*Patient Global+0.07*Peripheral Pain/Swelling+0.58*ln(CRP+1). | Week 8 | 
| Change From Baseline in ASDAS CRP Score at Weeks 12 and 16. | The ASDAS-CRP was derived from back pain, duration of morning stiffness, patient global score and peripheral pain/swelling. The scores were categorized as follows : inactive disease(< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity ( > 3.5). ASDAS CRP is calculated as follows: ASDAS CRP=0.12*Total Back Pain+0.06*Duration of Morning Stiffness+0.11*Patient Global+0.07*Peripheral Pain/Swelling+0.58*ln(CRP+1). | Weeks 12 and 16 | 
| Change From Baseline in ASDAS ESR (Ankylosing Spondylitis Disease Activity Score-Erythrocyte Sedimentation Rate) Score at Week 4. | The ASDAS-ESR was derived from back pain, duration of morning stiffness, patient global score and peripheral pain/swelling. The scores were categorized as follows : inactive disease (< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity ( > 3.5). ASDAS ESR is calculated as follows: ASDAS ESR=0.08*Total Back Pain+0.07*Duration of Morning Stiffness+0.11*Patient Global+0.09*Peripheral Pain/Swelling+0.29*√(ESR). | Week 4 | 
| Change From Baseline in ASDAS ESR Score at Week 8. | The ASDAS-ESR was derived from back pain, duration of morning stiffness, patient global score and peripheral pain/swelling. The scores were categorized as follows : inactive disease (< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity ( > 3.5). ASDAS ESR is calculated as follows: ASDAS ESR=0.08*Total Back Pain+0.07*Duration of Morning Stiffness+0.11*Patient Global+0.09*Peripheral Pain/Swelling+0.29*√(ESR). | Week 8 | 
| Change From Baseline in ASDAS ESR Score at Weeks 12 and 16. | The ASDAS-ESR was derived from back pain, duration of morning stiffness, patient global score and peripheral pain/swelling. The scores were categorized as follows : inactive disease (< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity ( > 3.5). ASDAS ESR is calculated as follows: ASDAS ESR=0.08*Total Back Pain+0.07*Duration of Morning Stiffness+0.11*Patient Global+0.09*Peripheral Pain/Swelling+0.29*√(ESR). | Weeks 12 and 16 | 
| Change in NSAID ASAS Score From Baseline to Week 16 (ETN Arm Only) | Diary data from the 7 days prior to respective visit were used to evaluate the endpoint, where the score was only calculated if at least 5 of the 7 days data were available. Score was calculated from NSAID usage completed on diary cards considering NSAID type, total daily dose and number of days consumed. The Daily diclofenac-equivalent dose score was derived by converting each daily dose of NSAID to a percentage dose equivalent of 150 mg diclofenac; e.g. 1000 mg naproxen is equivalent to 150 mg diclofenac. For each NSAID, the percentage diclofenac-equivalent score is then multiplied by daily dose frequency and proportion of the period where dose was taken. Ie Score=M x F x n/N (M: Percentage dose equivalent to diclofenac; F=Daily Dose Frequency; n=number of days with NSAID; N=number of days in period). The NSAID ASAS score is the sum of all such scores for all NSAIDs taken during the period. The minimum value is 0 and a higher NSAID-ASAS value indicates greater NSAIDs consumption. | Week 16 | 
| Change in NSAID ASAS Score From Week 8 to Week 16 (Placebo Only) | Diary data from the 7 days prior to respective visit were used to evaluate the endpoint, where the score was only calculated if at least 5 of the 7 days data were available. Score was calculated from NSAID usage completed on diary cards considering NSAID type, total daily dose and number of days consumed. The Daily diclofenac-equivalent dose score was derived by converting each daily dose of NSAID to a percentage dose equivalent of 150 mg diclofenac; e.g. 1000 mg naproxen is equivalent to 150 mg diclofenac. For each NSAID, the percentage diclofenac-equivalent score is then multiplied by daily dose frequency and proportion of the period where dose was taken. Ie Score=M x F x n/N (M: Percentage dose equivalent to diclofenac; F=Daily Dose Frequency; n=number of days with NSAID; N=number of days in period). The NSAID ASAS score is the sum of all such scores for all NSAIDs taken during the period. The minimum value is 0 and a higher NSAID-ASAS value indicates greater NSAIDs consumption. | Week 16 | 
| Change From Baseline in BASDAI Level of Morning Stiffness-related Scores at Week 8 | Participants were requested to complete the BASDAI upon symptom return then every day for the first 15 days after first administration of test article and weekly thereafter. A numeric rating scale was used, for questions 1-5 (Fatigue, Spinal Pain, Joint pain or swelling, discomfort and morning stiffness severity respectively) it was on the scale from 0 (none) to 10 (very severe). For question 6 (morning stiffness duration) it was on the scale of 0 (0 or more hours) to 10 (2 hours). The analysis presented below is the change in morning stiffness severity. | Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Etanercept, Axial Spondyloarthritis, NSAIDs sparing effect