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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00809159
First received: December 16, 2008
Last updated: December 7, 2015
Last verified: August 2015
  Purpose
Evaluate the safety, tolerability and pharmacokinetics of AIN457 when administered as treatment of moderate to severe ankylosing spondylitis (AS).

Condition Intervention Phase
Ankylosing Spondylitis
Biological: AIN457
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: Randomized, Placebo Controlled Double Blind, Multi-center Phase II Proof-of-concept Study to Assess the Efficacy of AIN457 in Patients With Moderate to Severe Ankylosing Spondylitis

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Percentage of Participants Who Achieved ASAS20 Response [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]
    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:
  • Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 Over Time in Part 1 [ Time Frame: Day8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, week 6, week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, day 8,15,29, week 6,8,10,12,16,20,24,28 ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in Part 1 and 2 [ Time Frame: Baseline, day 8,15,29,week 6,8,10,12,16,20,24,28 ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1 [ Time Frame: Baseline, day 8,15,29,week, 6, 8,10,12,16,20,24,28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 8,15,29,week, 6, 10,12,16,20,24,28 ] [ Designated as safety issue: No ]
    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 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. [ Time Frame: SF-36:Baseline, week 12, week 28; ASQoL: Baseline, Day 29, week 12, week 28 ] [ Designated as safety issue: No ]
    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. [ Time Frame: SF-36: Baseline, week 12, week 28; ASQoL: Baseline, day 29, week 12, week 8 ] [ Designated as safety issue: No ]
    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.


Enrollment: 60
Study Start Date: March 2009
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1 - AIN457A 10 mg/kg
AIN457A 10.0 mg/kg was administered intravenously as a single dose.
Biological: AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
Placebo Comparator: Part 1 - Placebo
Placebo to AIN457A was administered intravenously as a single dose
Drug: Placebo
Placebo to AIN457
Experimental: Parts 1 and 2 - AIN457A 1.0 mg/kg
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.
Biological: AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
Experimental: Part 1 and 2 - AIN457 0.1 mg/kg
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.
Biological: AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
Experimental: Part 1 and 2 - AIN457 10 mg/kg
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.
Biological: AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00809159

Locations
United States, Arizona
Novartis Investigative Site
Paradise Valley, Arizona, United States, 85253
United States, Illinois
Novartis Investigative Site
Springfield, Illinois, United States, 62703
Novartis Investigative Site
Springfield, Illinois, United States, 62704
United States, Oklahoma
Novartis Investigative Site
Oklahoma City, Oklahoma, United States, 73112
United States, Pennsylvania
Novartis Investigative Site
Duncansville, Pennsylvania, United States, 16635
United States, South Carolina
Novartis Investigative Site
North Charleston, South Carolina, United States, 29406
United States, Tennessee
Novartis Investigative Site
Jackson, Tennessee, United States, 38305
Novartis Investigative Site
Knoxville, Tennessee, United States, 37909
United States, Texas
Novartis Investigative Site
Benbrook, Texas, United States, 76126
United States, Washington
Novartis Investigative Site
Spokane, Washington, United States, 99204
Germany
Novartis Investigative Site
Berlin, Germany, 12200
Novartis Investigative Site
Hamburg, Germany, 22081
Novartis Investigative Site
Herne, Germany, 44649
Novartis Investigative Site
Munchen, Germany, D-80639
Netherlands
Novartis Investigative Site
Meerssen, KR, Netherlands, 6231
Novartis Investigative Site
Amstedam, Netherlands, 22700
Novartis Investigative Site
Maastricht, Netherlands, 5800
United Kingdom
Novartis Investigative Site
Leeds, United Kingdom, LS7 4SA
Novartis Investigative Site
Newcastle upon Tyne, United Kingdom, NE2 4HH
Novartis Investigative Site
Oxford, United Kingdom, OX3 7LD
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00809159     History of Changes
Other Study ID Numbers: CAIN457A2209  2008-002631-33 
Study First Received: December 16, 2008
Results First Received: January 29, 2015
Last Updated: December 7, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
ankylosing spondylitis

Additional relevant MeSH terms:
Spondylitis
Spondylitis, Ankylosing
Ankylosis
Arthritis
Bone Diseases
Bone Diseases, Infectious
Infection
Joint Diseases
Musculoskeletal Diseases
Spinal Diseases
Spondylarthritis
Spondylarthropathies

ClinicalTrials.gov processed this record on February 09, 2016