Double Blind, Placebo Controlled Study to Assess Efficacy of AIN457 in Moderate to Severe Ankylosing Spondylitis

Novartis Pharmaceuticals60 enrolled

Overview

Evaluate the safety, tolerability and pharmacokinetics of AIN457 when administered as treatment of moderate to severe ankylosing spondylitis (AS).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Masking

DOUBLE

Enrollment

Conditions

Ankylosing Spondylitis

Interventions

AIN457BIOLOGICAL

AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.

PlaceboDRUG

Placebo to AIN457

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients with moderate to severe AS fulfilling the modified New York criteria for a diagnosis of AS and whose disease was not controlled on NSAIDS (on at least one NSAID over a period of at least 3 months at maximum dose). Minimum disease activity for inclusion of patients was assessed based on the ASAS core set domains: back pain \& nocturnal pain score ≥ 4 despite concurrent NSAID use, PLUS a BASDAI score ≥ 4. Elevated CRP or ESR was not mandatory for study inclusion * No evidence of liver disease or liver injury as indicated by abnormal liver function tests such as serum glutamic oxaloacetic transaminase (SGOT/AST), serum glutamic pyruvic transaminase (SGPT/ALT), gamma glutamyl transpeptidase (GGT), alkaline phosphatase, or serum bilirubin. The investigator was guided by criteria as outlined under exclusion criteria Exclusion Criteria: * For patients who were previously treated with TNF blockers, the following washout periods were required for these patients to be eligible to participate in the trial: * month washout period prior to baseline for alefacept * month washout period prior to baseline for adalimumab and certolizumab * month washout prior to baseline for etanercept or infliximab * For patients who were previously treated with immunosuppressive agents other than MTX, SSZ, and systemic corticosteroids, a 1-month washout period prior to baseline was required. Immunosuppressive agents included but were not limited to cyclosporine, mycophenolate, tacrolimus, and 5-aminosalicylic acid (5-ASA). Prednisone had to be kept at a stable dose 4 weeks before baseline and throughout the study and not to exceed 10 mg/day. * MTX had to be kept at a stable dose 4 weeks before baseline and throughout the study and not to exceed 25 mg/week. * SSZ had to be kept at a stable dose 4 weeks before baseline and throughout the study. * In case of previous leflunomide treatment, a wash-out with oral cholestyramine could be considered as an alternative wash-out procedure to increase the elimination of leflunomide. Based on the notion that cholestyramine reduces plasma levels of the active leflunomide metabolite by approximately 40% in 24 hours and by 49% in 48 hours, cholestyramine was to be given orally at a dose of 8 g t.i.d. daily for 10 days. The patient could then be dosed with study drug not earlier than 2 weeks after the start of the cholestyramine wash-out procedure. * Patients who were on NSAIDs had to be kept at a stable dose 4 weeks prior to baseline and throughout the study. * Positive human immunodeficient virus (HIV: ELISA and Western blot) test result, Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. Any active systemic infection within the past 2 weeks including a positive chest X-ray. * Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, psychiatric, chronic inflammatory diseases with the exception of psoriatic arthritis or other disease which in the clinical judgment of the investigator would make the patient unsuitable for the trial

Locations (20)

Novartis Investigative Site

Paradise Valley, Arizona, United States

Novartis Investigative Site

Springfield, Illinois, United States

Outcomes

Primary Outcomes

Percentage of Participants Who Achieved ASAS20 Response

Clinical response to treatment was assessed according to ASAS20 criteria. ASAS20 responder had improvement of 20% or more and absolute improvement of at least 1 units (on a scale of 0 \[least\] to 10 \[worst\]) from Baseline in at least 3 of the following 4 domains, with absence of deterioration (worsening of at least 20% an absolute Worsening of at least 1 unit) in the potential remaining domain: Patient's Global Assessment of Disease Activity; Total Back Pain visual analog scale (VAS); Function (Bath Ankylosing Spondylitis Functional Index (BASFI)); and Inflammation (mean of 2 morning stiffness-related Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] scores

Time frame: 6 Weeks

Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score From Baseline to 6 Weeks After First Infusion in Part 2

ASAS20 as described in Primary Outcome. ASAS40 responder had improvement of 40% or more and absolute improvement of at least 2 units (on a scale of 0 \[least\] to 10 \[worst\]) from Baseline in at least 3 of the following 4 domains, with no deterioration in the potential remaining domain: Patient's Global Assessment of Disease Activity; Total Back Pain visual analog scale (VAS); Function (Bath Ankylosing Spondylitis Functional Index (BASFI)); and Inflammation (mean of 2 morning stiffness-related Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] scores). ASAS 5/6 responder had improvement of 20% or more) from Baseline in at least 5 of the following 6 domains: Patient's Global Assessment of Disease Activity; Total Back Pain visual analog scale (VAS); Function (BASFI); and Inflammation (mean of 2 morning stiffness-related Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] scores); Spinal Mobility (BASFI); Acute phase reactant (CRP)

Time frame: 6 Weeks

Secondary Outcomes

Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 Over Time in Part 1

ASAS20 responder had improvement of 40% or more and absolute improvement of at least 2 units (scale of 0 \[least\] to 10 \[worst\]) from Baseline in at least 3 of the following 4 domains, with no deterioration in the potential remaining domain: Patient's Global Assessment of Disease Activity; Total Back Pain visual analog scale (VAS); Function (Bath Ankylosing Spondylitis Functional Index (BASFI)); and Inflammation (mean of 2 morning stiffness-related Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] scores). ASAS 5/6 responder had improvement of 20% or more) from Baseline in at least 5 of the following 6 domains: Patient's Global Assessment of Disease Activity; Total Back Pain visual analog scale (VAS); Function (Bath Ankylosing Spondylitis Functional Index (BASFI)); and Inflammation (mean of 2 morning stiffness-related Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] scores); Spinal Mobility (BASFI); Acute phase reactant (CRP)

Data from ClinicalTrials.gov

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Novartis Investigative Site

Springfield, Illinois, United States

Novartis Investigative Site

Oklahoma City, Oklahoma, United States

Novartis Investigative Site

Duncansville, Pennsylvania, United States

Novartis Investigative Site

North Charleston, South Carolina, United States

Novartis Investigative Site

Jackson, Tennessee, United States

Novartis Investigative Site

Knoxville, Tennessee, United States

Novartis Investigative Site

Benbrook, Texas, United States

Novartis Investigative Site

Spokane, Washington, United States

...and 10 more locations

Time frame: Day8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28

Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 in Part 1 and 2 Combined

a Bayesian model was fitted to the ASAS20 , ASAS40 and ASAS 5/6 response rates on active and placebo treatments. A Bayesian analysis had been chosen to allow the direct incorporation into the analysis of information about placebo response rates from historical data

Time frame: Day 8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28

Magnetic Resonance Imaging (MRI) Inflammatory Scores at Baseline, Week 6 in Part 1

The study used MRI with fat-saturating techniques such as short tau inversion recovery (STIR) to look for the presence of bone marrow edema. The Berlin modification of ASspiMRI-a (ASspiMRI-a) scoring technique assesses inflammation in each of the 23 disc vertebral units (DVU), capturing edema and erosion. Scores for each DVU range from 0-3 (0=normal; 1=minor bone marrow edema (less than25% of DVU; 3=severe bone marrow edema (more that 50% of DVU). The composite score ranges from 0 to 69, with higher scores indicating more severe inflammation

Time frame: Baseline, week 6, week 28

Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1

Serum samples were collected pre-dose 2, 3, 4 and 24 hours after initiation of the infusions (Days 1 and 22), Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 and end of study/Week 28.

Time frame: Week 28

Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 and 2

Serum samples were collected pre-dose 2, 3, 4 and 24 hours after initiation of the infusions (Days 1 and 22), Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 and end of study/Week 28.

Time frame: Week 28

PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1