Clinical trial NCT00809159: Double Blind, Placebo Controlled Study to Assess Efficacy of AIN457 in Moderate to Severe Ankylosing Spondylitis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ankylosing Spondylitis
Keywords: ankylosing spondylitis
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-12-17
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL

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


Eligibility 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

Primary outcomes:
measure: Percentage of Participants Who Achieved ASAS20 Response
timeFrame: 6 Weeks
measure: Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score From Baseline to 6 Weeks After First Infusion in Part 2
timeFrame: 6 Weeks
Secondary outcomes:
measure: Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 Over Time in Part 1
timeFrame: Day8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28
measure: Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 in Part 1 and 2 Combined
timeFrame: Day 8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28
measure: Magnetic Resonance Imaging (MRI) Inflammatory Scores at Baseline, Week 6 in Part 1
timeFrame: Baseline, week 6, week 28
measure: Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1
timeFrame: Week 28
measure: Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 and 2
timeFrame: Week 28
measure: PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1
timeFrame: Week 28
measure: PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 and 2
timeFrame: Week 28
measure: 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
timeFrame: Week 28
measure: 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
timeFrame: Week 28
measure: PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1
timeFrame: Week 28
measure: PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 and 2
timeFrame: Week 28
measure: PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1
timeFrame: Week 28
measure: PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 and 2
timeFrame: Week 28
measure: PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1
timeFrame: Week 28
measure: PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 and 2
timeFrame: Week 28
measure: Mean Change Bath Ankylosing Spondylitis Metrology Index (BASMI) Score in Part 1 and 2
timeFrame: Baseline, day 8,15,29, week 6,8,10,12,16,20,24,28
measure: Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in Part 1 and 2
timeFrame: Baseline, day 8,15,29,week 6,8,10,12,16,20,24,28
measure: Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1
timeFrame: Baseline, day 8,15,29,week, 6, 8,10,12,16,20,24,28
measure: Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1 and 2
timeFrame: Day 8,15,29,week, 6, 10,12,16,20,24,28
measure: 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.
timeFrame: SF-36:Baseline, week 12, week 28; ASQoL: Baseline, Day 29, week 12, week 28
measure: 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.
timeFrame: SF-36: Baseline, week 12, week 28; ASQoL: Baseline, day 29, week 12, week 8
Other outcomes:
Locations:
city: Paradise Valley
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Springfield
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Springfield
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Oklahoma City
country: United States
facility: Novartis Investigative Site
state: Oklahoma
city: Duncansville
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: North Charleston
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Jackson
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Knoxville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Benbrook
country: United States
facility: Novartis Investigative Site
state: Texas
city: Spokane
country: United States
facility: Novartis Investigative Site
state: Washington
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Herne
country: Germany
facility: Novartis Investigative Site
city: Munchen
country: Germany
facility: Novartis Investigative Site
city: Meerssen
country: Netherlands
facility: Novartis Investigative Site
state: KR
city: Amstedam
country: Netherlands
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Baraliakos X, Borah B, Braun J, Baeten D, Laurent D, Sieper J, Emery P, McInnes IB, van Laar JM, Wordsworth P, Wollenhaupt J, Kellner H, Colin L, Vandenhende F, Radford K, Hueber W. Long-term effects of secukinumab on MRI findings in relation to clinical efficacy in subjects with active ankylosing spondylitis: an observational study. Ann Rheum Dis. 2016 Feb;75(2):408-12. doi: 10.1136/annrheumdis-2015-207544. Epub 2015 Aug 6.
citation: Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, van der Heijde D, McInnes I, van Laar JM, Landewe R, Wordsworth P, Wollenhaupt J, Kellner H, Paramarta J, Wei J, Brachat A, Bek S, Laurent D, Li Y, Wang YA, Bertolino AP, Gsteiger S, Wright AM, Hueber W. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2013 Nov 23;382(9906):1705-13. doi: 10.1016/S0140-6736(13)61134-4. Epub 2013 Sep 13.