Adalimumab for Non-radiographic Axial Spondyloarthritis
Adalimumab for Non-radiographic Axial Spondyloarthritis
Eligible patients were ≥18 years of age and fulfilled ASAS classification criteria for axial SpA without meeting modified New York criteria for AS. Patients must have had active disease, exhibited by a total back pain score of ≥4 on a 0–10 cm visual analogue scale (VAS) (≥40 on a 0–100 mm VAS) and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥4. They must also have responded inadequately or been intolerant to one or more NSAIDs, or had a contraindication to NSAIDs based on the clinical judgment of the investigator. Patients with previous or current diagnoses of psoriasis or psoriatic arthritis or a history of inflammatory arthritis of a different aetiology were excluded. Previous exposure to biological agents was not permitted.
ABILITY-1 (NCT00939003) was initiated in August 2009 and is an ongoing phase III randomised placebo-controlled double-blind trial conducted at 37 centres in Australia, Belgium, Canada, Czech Republic, France, Germany, Spain, The Netherlands, the UK and the USA. It was conducted in accordance with International Conference on Harmonization good clinical practices and the Declaration of Helsinki. Approval of an institutional ethics review board and voluntary written informed patient consent were obtained prior to study procedures.
Eligible patients were centrally randomised using an interactive voice response system 1:1 to receive subcutaneous injections of adalimumab (40 mg every other week) or matching placebo for 12 weeks during the double-blind period. Efficacy and safety were assessed at weeks 2, 4, 8 and 12. Patients who completed the double-blind period were eligible to receive open-label adalimumab for up to an additional 144 weeks.
Patients could enter the study on concomitant NSAIDs, prednisone (≤10 mg per day), methotrexate (MTX, ≤25 mg per week), sulfasalazine (SSZ, ≤3 g per day) and/or hydroxychloroquine (≤400 mg per day) or azathioprine (≤150 mg per day, but not concomitant with any other DMARD) if the doses met pre-specified stability requirements prior to randomisation and remained stable during the first 24 weeks except as medically required due to an adverse event (AE).
Primary Efficacy Endpoint. The primary efficacy endpoint was the proportion of patients who achieved an ASAS40 response at week 12. An ASAS40 response was defined as a ≥40% improvement and an absolute improvement from baseline of ≥2 units (range 0–10) in ≥3 of the following four domains: Patient Global Assessment of Disease Activity (0–10 cm VAS), pain (total back pain, 0–10 cm VAS), function (Bath Ankylosing Spondylitis Functional Index (BASFI), 0–10 cm VAS) and inflammation/morning stiffness (mean score of items 5 and 6 of the BASDAI (0–10 cm VAS)) without any worsening in the remaining domain.
Secondary Efficacy Endpoints. Secondary efficacy variables analysed at week 12 included: ASAS20, ASAS partial remission (ASAS PR), ASAS5/6, BASDAI (0–10 cm VAS), BASDAI50, Ankylosing Spondylitis Disease Activity Score (ASDAS), ASDAS clinically important improvement (ASDAS CII, decrease from baseline ≥1.1), ASDAS major improvement (ASDAS MI, decrease from baseline ≥2.0), ASDAS inactive disease (ASDAS ID, score <1.3), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES, 0–13), linear Bath Ankylosing Spondylitis Metrology index (BASMIlin, 0–10), 36-Item Short Form V.2 Health Survey (SF-36), Health Assessment Questionnaire modified for Spondyloarthropathies (HAQ-S) and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores for the sacroiliac (SI) joints (0–72) and the spine (0–108). MRI films were scored by two independent central readers who were blinded to time point and sequence. Average scores of the readers were used.
Treatment-emergent AEs were defined as AEs that began or worsened after the first dose of study medication through 70 days after the last dose.
Efficacy variables were analysed for all randomised patients who received at least one dose of blinded study medication, but excluding seven patients from one site due to investigator non-compliance. The safety population consisted of all patients who received at least one dose of study medication.
A target sample size of 194 patients (97 placebo and 97 adalimumab) was calculated to provide approximately 90% statistical power to detect a 20% difference in ASAS40 response rates between the treatment groups, based on a two-sided χ test with a significance level of 0.05.
For categorical variables, patients with missing data at week 12 were considered to be non-responders using non-responder imputation (NRI). Last observation carried forward imputed values were used for continuous variables. Analysis of covariance (ANCOVA) adjusting for the baseline score was used to compare change from baseline at week 12 between adalimumab and placebo treatment groups. VAS data were collected on 0–100 mm scales and reported as 0–10 cm data for consistency.
To evaluate the impact of baseline demographics and disease conditions on the primary efficacy endpoint, ASAS40 response at week 12 was summarised by subgroups of sex (male, female), race (white, non-white), age (<40, ≥40 years), weight (<70, ≥70 kg), symptom duration (<5, ≥5 years), baseline C-reactive protein (CRP) (normal, elevated), concomitant baseline NSAID use (yes, no) or DMARD use (yes, no), history of inflammatory bowel disease (yes, no) or uveitis (yes, no), baseline HLA-B27 status (positive, negative), past or current MRI evidence of inflammation of the SI joints according to the local radiologist/rheumatologist (positive, negative) and baseline SPARCC SI joint score (<2, ≥2). For subgroup analyses, a logistic model was used to assess treatment and subgroup interaction, with a significant interaction defined as p≤0.10.
AEs were summarised as the number and percentage of patients experiencing AEs using Medical Dictionary for Regulatory Activities (MedDRA, V.13.1) system organ classes and preferred terms.
Methods
Patients
Eligible patients were ≥18 years of age and fulfilled ASAS classification criteria for axial SpA without meeting modified New York criteria for AS. Patients must have had active disease, exhibited by a total back pain score of ≥4 on a 0–10 cm visual analogue scale (VAS) (≥40 on a 0–100 mm VAS) and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥4. They must also have responded inadequately or been intolerant to one or more NSAIDs, or had a contraindication to NSAIDs based on the clinical judgment of the investigator. Patients with previous or current diagnoses of psoriasis or psoriatic arthritis or a history of inflammatory arthritis of a different aetiology were excluded. Previous exposure to biological agents was not permitted.
Study Design
ABILITY-1 (NCT00939003) was initiated in August 2009 and is an ongoing phase III randomised placebo-controlled double-blind trial conducted at 37 centres in Australia, Belgium, Canada, Czech Republic, France, Germany, Spain, The Netherlands, the UK and the USA. It was conducted in accordance with International Conference on Harmonization good clinical practices and the Declaration of Helsinki. Approval of an institutional ethics review board and voluntary written informed patient consent were obtained prior to study procedures.
Eligible patients were centrally randomised using an interactive voice response system 1:1 to receive subcutaneous injections of adalimumab (40 mg every other week) or matching placebo for 12 weeks during the double-blind period. Efficacy and safety were assessed at weeks 2, 4, 8 and 12. Patients who completed the double-blind period were eligible to receive open-label adalimumab for up to an additional 144 weeks.
Patients could enter the study on concomitant NSAIDs, prednisone (≤10 mg per day), methotrexate (MTX, ≤25 mg per week), sulfasalazine (SSZ, ≤3 g per day) and/or hydroxychloroquine (≤400 mg per day) or azathioprine (≤150 mg per day, but not concomitant with any other DMARD) if the doses met pre-specified stability requirements prior to randomisation and remained stable during the first 24 weeks except as medically required due to an adverse event (AE).
Efficacy Endpoints
Primary Efficacy Endpoint. The primary efficacy endpoint was the proportion of patients who achieved an ASAS40 response at week 12. An ASAS40 response was defined as a ≥40% improvement and an absolute improvement from baseline of ≥2 units (range 0–10) in ≥3 of the following four domains: Patient Global Assessment of Disease Activity (0–10 cm VAS), pain (total back pain, 0–10 cm VAS), function (Bath Ankylosing Spondylitis Functional Index (BASFI), 0–10 cm VAS) and inflammation/morning stiffness (mean score of items 5 and 6 of the BASDAI (0–10 cm VAS)) without any worsening in the remaining domain.
Secondary Efficacy Endpoints. Secondary efficacy variables analysed at week 12 included: ASAS20, ASAS partial remission (ASAS PR), ASAS5/6, BASDAI (0–10 cm VAS), BASDAI50, Ankylosing Spondylitis Disease Activity Score (ASDAS), ASDAS clinically important improvement (ASDAS CII, decrease from baseline ≥1.1), ASDAS major improvement (ASDAS MI, decrease from baseline ≥2.0), ASDAS inactive disease (ASDAS ID, score <1.3), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES, 0–13), linear Bath Ankylosing Spondylitis Metrology index (BASMIlin, 0–10), 36-Item Short Form V.2 Health Survey (SF-36), Health Assessment Questionnaire modified for Spondyloarthropathies (HAQ-S) and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores for the sacroiliac (SI) joints (0–72) and the spine (0–108). MRI films were scored by two independent central readers who were blinded to time point and sequence. Average scores of the readers were used.
Safety Assessments
Treatment-emergent AEs were defined as AEs that began or worsened after the first dose of study medication through 70 days after the last dose.
Statistical Analysis
Efficacy variables were analysed for all randomised patients who received at least one dose of blinded study medication, but excluding seven patients from one site due to investigator non-compliance. The safety population consisted of all patients who received at least one dose of study medication.
A target sample size of 194 patients (97 placebo and 97 adalimumab) was calculated to provide approximately 90% statistical power to detect a 20% difference in ASAS40 response rates between the treatment groups, based on a two-sided χ test with a significance level of 0.05.
For categorical variables, patients with missing data at week 12 were considered to be non-responders using non-responder imputation (NRI). Last observation carried forward imputed values were used for continuous variables. Analysis of covariance (ANCOVA) adjusting for the baseline score was used to compare change from baseline at week 12 between adalimumab and placebo treatment groups. VAS data were collected on 0–100 mm scales and reported as 0–10 cm data for consistency.
To evaluate the impact of baseline demographics and disease conditions on the primary efficacy endpoint, ASAS40 response at week 12 was summarised by subgroups of sex (male, female), race (white, non-white), age (<40, ≥40 years), weight (<70, ≥70 kg), symptom duration (<5, ≥5 years), baseline C-reactive protein (CRP) (normal, elevated), concomitant baseline NSAID use (yes, no) or DMARD use (yes, no), history of inflammatory bowel disease (yes, no) or uveitis (yes, no), baseline HLA-B27 status (positive, negative), past or current MRI evidence of inflammation of the SI joints according to the local radiologist/rheumatologist (positive, negative) and baseline SPARCC SI joint score (<2, ≥2). For subgroup analyses, a logistic model was used to assess treatment and subgroup interaction, with a significant interaction defined as p≤0.10.
AEs were summarised as the number and percentage of patients experiencing AEs using Medical Dictionary for Regulatory Activities (MedDRA, V.13.1) system organ classes and preferred terms.
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