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

Phase 2

Completed

Conditions: Ankylosing Spondylitis

Interventions: Biological: AIN457
Drug: Placebo

Registration Number: NCT00809159

Lead Sponsor: Novartis Pharmaceuticals

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Parts 1 and 2 - AIN457A 1.0 mg/kg	AIN457	AIN457A 1.0 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22.
Part 1 - AIN457A 10 mg/kg	AIN457	AIN457A 10.0 mg/kg was administered intravenously as a single dose.
Part 1 - Placebo	Placebo	Placebo to AIN457A was administered intravenously as a single dose
Part 1 and 2 - AIN457 0.1 mg/kg	AIN457	AIN457A 0.1 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22.
Part 1 and 2 - AIN457 10 mg/kg	AIN457	AIN457A 10.0 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Achieved ASAS20 Response	6 Weeks	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
Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score From Baseline to 6 Weeks After First Infusion in Part 2	6 Weeks	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)

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 Over Time in Part 1	Day8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28	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)
Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 in Part 1 and 2 Combined	Day 8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28	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
Magnetic Resonance Imaging (MRI) Inflammatory Scores at Baseline, Week 6 in Part 1	Baseline, week 6, week 28	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
Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1	Week 28	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.
Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 and 2	Week 28	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.
PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1	Week 28	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
PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 and 2	Week 28	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
PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1	Week 28	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
PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 and 2	Week 28	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
PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1	Week 28	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
PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 and 2	Week 28	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
PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1	Week 28	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
PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 and 2	Week 28	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
PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1	Week 28	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
PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 and 2	Week 28	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
Mean Change Bath Ankylosing Spondylitis Metrology Index (BASMI) Score in Part 1 and 2	Baseline, day 8,15,29, week 6,8,10,12,16,20,24,28	BASMI measures the range of motion based on five clinical measurements: 1) cervical rotation, 2) tragus to wall distance, 3) lumbar side flexion, 4) lumbar flexion (modified Schober's) and 5) intermalleolar distance. BASMI 0 = indicates mild disease involvement, 1 = moderate disease, and 2 = severe disease involvement. The results for cervical rotation and lumbar side flexion are the means of the left and right measurements. Scoring range 0-10. The higher the BASMI score, the more severe was the subject's limitation of movement
Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1	Baseline, day 8,15,29,week, 6, 8,10,12,16,20,24,28	MASES is measured by scoring of entheses of 0 (no tenderness) to 3 (severe tenderness) at 13 sites on the body. The score was derived as the sum of the 13 scores divided by 3 and the total range is 0 (no tenderness) to 13 (severe tenderness).
Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1 and 2	Day 8,15,29,week, 6, 10,12,16,20,24,28	MASES is measured by scoring of entheses of 0 (no tenderness) to 3 (severe tenderness) at 13 sites on the body. The score was derived as the sum of the 13 scores divided by 3 and the total range is 0 (no tenderness) to 13 (severe tenderness).
Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in Part 1 and 2	Baseline, day 8,15,29,week 6,8,10,12,16,20,24,28	The BASDAI consists of a 1 through 10 scale (1 being no problem and 10 being the worst problem), which was used to answer 6 questions pertaining to the 5 major symptoms of AS: Fatigue, Spinal pain, Joint pain / swelling, areas of localized tenderness (called enthesitis, or inflammation of insertion sites of tendons and ligaments), morning stiffness duration, and morning stiffness severity. The physician will globally assess the subject's current disease state using a visual analog scale (VAS) scale with 0 being very good and 100 being very bad.
Change From Baseline in the Health Related Quality of Life (HRQoL) by Using the SF-36 Physical Component, and the ASQoL (Ankylosing Spondylitis Quality of Life Instrument) in Part 1.	SF-36:Baseline, week 12, week 28; ASQoL: Baseline, Day 29, week 12, week 28	The Short Form (36) Health Survey (SF-36) measures the impact of disease on overall quality of life and consists of eight subscales (physical function, pain, general and mental health, vitality, social function, physical and emotional health) which can be aggregated to derive a physical-component summary score and a mental-component summary score. Scores range for each subscale from 0 to 10, and the composite score ranges from 0 to 100, with higher scores indicative of better health. ASQoL determined subject's quality of life and is comprised of 18 questions (yes or no) to be completed by the subject. Each statement on the ASQoL is given a score of "1" or "0." All item scores were summed to give a total score or index. Total scores ranged from 0 (good quality of life) to 18 (poor quality of life) related to ability to cope, relationships, mood, sleep, motivation, activities of everyday living, independence, and social life. Decrease in ASQoL score represents improvement.
Change From Baseline in the Health Related Quality of Life (HRQoL) by Using the SF-36 Physical Component, and the ASQoL (Ankylosing Spondylitis Quality of Life Instrument) in Part 1 and 2.	SF-36: Baseline, week 12, week 28; ASQoL: Baseline, day 29, week 12, week 8	The SF-36 measures the impact of disease on overall quality of life and consists of eight subscales (physical function, pain, general and mental health, vitality, social function, physical and emotional health) which can be aggregated to derive a physical-component summary score and a mental-component summary score. ASQoL determined subject's quality of life and is comprised of 18 questions (yes or no) to be completed by the subject. Each statement on the ASQoL is given a score of "1" or "0." All item scores were summed to give a total score or index. Total scores ranged from 0 (good quality of life) to 18 (poor quality of life) related to ability to cope, relationships, mood, sleep, motivation, activities of everyday living, independence, and social life. Decrease in ASQoL score represents improvement.