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

7 december 2015 bijgewerkt door: 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).

Studie Overzicht

Toestand

Voltooid

Conditie

Interventie / Behandeling

Studietype

Ingrijpend

Inschrijving (Werkelijk)

60

Fase

  • Fase 2

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

  • Duitsland
      • Berlin, Duitsland, 12200
        • Novartis Investigative Site
      • Hamburg, Duitsland, 22081
        • Novartis Investigative Site
      • Herne, Duitsland, 44649
        • Novartis Investigative Site
      • Munchen, Duitsland, D-80639
        • Novartis Investigative Site
  • Nederland
      • Amstedam, Nederland, 22700
        • Novartis Investigative Site
      • Maastricht, Nederland, 5800
        • Novartis Investigative Site
    • KR
      • Meerssen, KR, Nederland, 6231
        • Novartis Investigative Site
  • Verenigd Koninkrijk
      • Leeds, Verenigd Koninkrijk, LS7 4SA
        • Novartis Investigative Site
      • Newcastle upon Tyne, Verenigd Koninkrijk, NE2 4HH
        • Novartis Investigative Site
      • Oxford, Verenigd Koninkrijk, OX3 7LD
        • Novartis Investigative Site
  • Verenigde Staten
    • Arizona
      • Paradise Valley, Arizona, Verenigde Staten, 85253
        • Novartis Investigative Site
    • Illinois
      • Springfield, Illinois, Verenigde Staten, 62704
        • Novartis Investigative Site
      • Springfield, Illinois, Verenigde Staten, 62703
        • Novartis Investigative Site
    • Oklahoma
      • Oklahoma City, Oklahoma, Verenigde Staten, 73112
        • Novartis Investigative Site
    • Pennsylvania
      • Duncansville, Pennsylvania, Verenigde Staten, 16635
        • Novartis Investigative Site
    • South Carolina
      • North Charleston, South Carolina, Verenigde Staten, 29406
        • Novartis Investigative Site
    • Tennessee
      • Jackson, Tennessee, Verenigde Staten, 38305
        • Novartis Investigative Site
      • Knoxville, Tennessee, Verenigde Staten, 37909
        • Novartis Investigative Site
    • Texas
      • Benbrook, Texas, Verenigde Staten, 76126
        • Novartis Investigative Site
    • Washington
      • Spokane, Washington, Verenigde Staten, 99204
        • Novartis Investigative Site

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

18 jaar tot 65 jaar (Volwassen, Oudere volwassene)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Toewijzing: Gerandomiseerd
  • Interventioneel model: Parallelle opdracht
  • Masker: Dubbele

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: Part 1 - AIN457A 10 mg/kg
AIN457A 10.0 mg/kg was administered intravenously as a single dose.
Biologisch: AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
Placebo-vergelijker: Part 1 - Placebo
Placebo to AIN457A was administered intravenously as a single dose
Geneesmiddel: Placebo
Placebo to AIN457
Experimenteel: 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.
Biologisch: AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
Experimenteel: 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.
Biologisch: AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
Experimenteel: 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.
Biologisch: AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Percentage of Participants Who Achieved ASAS20 Response
Tijdsspanne: 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
6 Weeks
Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score From Baseline to 6 Weeks After First Infusion in Part 2
Tijdsspanne: 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)
6 Weeks

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 Over Time in Part 1
Tijdsspanne: 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)
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
Tijdsspanne: 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
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
Tijdsspanne: 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
Baseline, week 6, week 28
Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1
Tijdsspanne: 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.
Week 28
Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 and 2
Tijdsspanne: 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.
Week 28
PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1
Tijdsspanne: 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
Week 28
PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 and 2
Tijdsspanne: 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
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
Tijdsspanne: 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
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
Tijdsspanne: 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
Week 28
PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1
Tijdsspanne: 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
Week 28
PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 and 2
Tijdsspanne: 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
Week 28
PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1
Tijdsspanne: 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
Week 28
PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 and 2
Tijdsspanne: 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
Week 28
PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1
Tijdsspanne: 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
Week 28
PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 and 2
Tijdsspanne: 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
Week 28
Mean Change Bath Ankylosing Spondylitis Metrology Index (BASMI) Score in Part 1 and 2
Tijdsspanne: 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
Baseline, day 8,15,29, week 6,8,10,12,16,20,24,28
Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in Part 1 and 2
Tijdsspanne: 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.
Baseline, day 8,15,29,week 6,8,10,12,16,20,24,28
Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1
Tijdsspanne: 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).
Baseline, day 8,15,29,week, 6, 8,10,12,16,20,24,28
Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1 and 2
Tijdsspanne: 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).
Day 8,15,29,week, 6, 10,12,16,20,24,28
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.
Tijdsspanne: 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.
SF-36:Baseline, week 12, week 28; ASQoL: Baseline, Day 29, week 12, week 28
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.
Tijdsspanne: 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.
SF-36: Baseline, week 12, week 28; ASQoL: Baseline, day 29, week 12, week 8

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Novartis Pharmaceuticals

Publicaties en nuttige links

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Algemene publicaties

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start

1 maart 2009

Primaire voltooiing (Werkelijk)

1 mei 2011

Studie voltooiing (Werkelijk)

1 mei 2011

Studieregistratiedata

Eerst ingediend

16 december 2008

Eerst ingediend dat voldeed aan de QC-criteria

16 december 2008

Eerst geplaatst (Schatting)

17 december 2008

Updates van studierecords

Laatste update geplaatst (Schatting)

9 december 2015

Laatste update ingediend die voldeed aan QC-criteria

7 december 2015

Laatst geverifieerd

1 augustus 2015

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • CAIN457A2209
  • 2008-002631-33

Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .

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