Double Blind, Placebo Controlled Study to Assess Efficacy of AIN457 in Moderate to Severe Ankylosing Spondylitis
2015年12月7日 更新者：Novartis Pharmaceuticals
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
Evaluate the safety, tolerability and pharmacokinetics of AIN457 when administered as treatment of moderate to severe ankylosing spondylitis (AS).
調査の概要
研究の種類
介入
入学 (実際)
60
段階
- フェーズ2
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究場所
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Arizona
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Paradise Valley、Arizona、アメリカ、85253
- Novartis Investigative Site
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Illinois
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Springfield、Illinois、アメリカ、62704
- Novartis Investigative Site
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Springfield、Illinois、アメリカ、62703
- Novartis Investigative Site
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Oklahoma
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Oklahoma City、Oklahoma、アメリカ、73112
- Novartis Investigative Site
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Pennsylvania
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Duncansville、Pennsylvania、アメリカ、16635
- Novartis Investigative Site
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South Carolina
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North Charleston、South Carolina、アメリカ、29406
- Novartis Investigative Site
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Tennessee
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Jackson、Tennessee、アメリカ、38305
- Novartis Investigative Site
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Knoxville、Tennessee、アメリカ、37909
- Novartis Investigative Site
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Texas
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Benbrook、Texas、アメリカ、76126
- Novartis Investigative Site
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Washington
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Spokane、Washington、アメリカ、99204
- Novartis Investigative Site
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Leeds、イギリス、LS7 4SA
- Novartis Investigative Site
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Newcastle upon Tyne、イギリス、NE2 4HH
- Novartis Investigative Site
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Oxford、イギリス、OX3 7LD
- Novartis Investigative Site
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Amstedam、オランダ、22700
- Novartis Investigative Site
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Maastricht、オランダ、5800
- Novartis Investigative Site
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KR
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Meerssen、KR、オランダ、6231
- Novartis Investigative Site
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Berlin、ドイツ、12200
- Novartis Investigative Site
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Hamburg、ドイツ、22081
- Novartis Investigative Site
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Herne、ドイツ、44649
- Novartis Investigative Site
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Munchen、ドイツ、D-80639
- Novartis Investigative Site
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参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
18年～65年 (大人、高齢者)
健康ボランティアの受け入れ
いいえ
受講資格のある性別
全て
説明
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
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：ダブル
武器と介入
参加者グループ / アーム |
介入・治療 |
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実験的：Part 1 - AIN457A 10 mg/kg
AIN457A 10.0 mg/kg was administered intravenously as a single dose.
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AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
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プラセボコンパレーター：Part 1 - Placebo
Placebo to AIN457A was administered intravenously as a single dose
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Placebo to AIN457
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実験的：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.
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AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
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実験的：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.
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AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
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実験的：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.
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AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Percentage of Participants Who Achieved ASAS20 Response
時間枠：6 Weeks
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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
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6 Weeks
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Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score From Baseline to 6 Weeks After First Infusion in Part 2
時間枠：6 Weeks
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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)
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6 Weeks
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 Over Time in Part 1
時間枠：Day8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28
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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)
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Day8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28
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Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 in Part 1 and 2 Combined
時間枠：Day 8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28
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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
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Day 8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28
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Magnetic Resonance Imaging (MRI) Inflammatory Scores at Baseline, Week 6 in Part 1
時間枠：Baseline, week 6, week 28
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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
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Baseline, week 6, week 28
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Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1
時間枠：Week 28
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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.
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Week 28
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Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 and 2
時間枠：Week 28
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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.
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Week 28
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PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1
時間枠：Week 28
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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
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Week 28
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PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 and 2
時間枠：Week 28
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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
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Week 28
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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
時間枠：Week 28
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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
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Week 28
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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
時間枠：Week 28
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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
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Week 28
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PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1
時間枠：Week 28
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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
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Week 28
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PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 and 2
時間枠：Week 28
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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
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Week 28
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PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1
時間枠：Week 28
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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
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Week 28
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PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 and 2
時間枠：Week 28
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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
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Week 28
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PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1
時間枠：Week 28
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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
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Week 28
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PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 and 2
時間枠：Week 28
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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
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Week 28
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Mean Change Bath Ankylosing Spondylitis Metrology Index (BASMI) Score in Part 1 and 2
時間枠：Baseline, day 8,15,29, week 6,8,10,12,16,20,24,28
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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
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Baseline, day 8,15,29, week 6,8,10,12,16,20,24,28
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Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in Part 1 and 2
時間枠：Baseline, day 8,15,29,week 6,8,10,12,16,20,24,28
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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.
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Baseline, day 8,15,29,week 6,8,10,12,16,20,24,28
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Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1
時間枠：Baseline, day 8,15,29,week, 6, 8,10,12,16,20,24,28
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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).
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Baseline, day 8,15,29,week, 6, 8,10,12,16,20,24,28
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Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1 and 2
時間枠：Day 8,15,29,week, 6, 10,12,16,20,24,28
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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).
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Day 8,15,29,week, 6, 10,12,16,20,24,28
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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.
時間枠：SF-36:Baseline, week 12, week 28; ASQoL: Baseline, Day 29, week 12, week 28
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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.
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SF-36:Baseline, week 12, week 28; ASQoL: Baseline, Day 29, week 12, week 28
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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.
時間枠：SF-36: Baseline, week 12, week 28; ASQoL: Baseline, day 29, week 12, week 8
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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.
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SF-36: Baseline, week 12, week 28; ASQoL: Baseline, day 29, week 12, week 8
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協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
スポンサー
出版物と役立つリンク
研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。
一般刊行物
- 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.
- 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. Erratum In: Lancet. 2014 May 3;383(9928):1548.
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始
2009年3月1日
一次修了 (実際)
2011年5月1日
研究の完了 (実際)
2011年5月1日
試験登録日
最初に提出
2008年12月16日
QC基準を満たした最初の提出物
2008年12月16日
最初の投稿 (見積もり)
2008年12月17日
学習記録の更新
投稿された最後の更新 (見積もり)
2015年12月9日
QC基準を満たした最後の更新が送信されました
2015年12月7日
最終確認日
2015年8月1日
詳しくは
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。