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Efficacy and Safety of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus

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ClinicalTrials.gov Identifier: NCT02446899
Recruitment Status : Completed
First Posted : May 18, 2015
Results First Posted : March 18, 2020
Last Update Posted : March 18, 2020
Sponsor:
Collaborator:
PRA Health Sciences
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE May 14, 2015
First Posted Date  ICMJE May 18, 2015
Results First Submitted Date  ICMJE March 5, 2020
Results First Posted Date  ICMJE March 18, 2020
Last Update Posted Date March 18, 2020
Actual Study Start Date  ICMJE July 9, 2015
Actual Primary Completion Date September 27, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2020)
Number of Participants Who Achieved the British Isles Lupus Assessment Group Based Composite Lupus Assessment (BICLA) Response at Week 52 [ Time Frame: Baseline; Week 52 ]
Composite endpoint BICLA, was defined by meeting all of the following criteria:
  • Reduction of all baseline British Isles Lupus Assessment Group (BILAG)-2004 A to B/C/D and baseline BILAG-2004 B to C/D, and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B
  • No worsening from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), where worsening is defined as an increase from baseline of >0 points in SLEDAI-2K
  • No worsening from baseline in participants' lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point Physician's Global Assessment (PGA) visual analogue scale (VAS)
  • No discontinuation of investigational product
  • No use of restricted medications beyond the protocol allowed threshold before assessment
Original Primary Outcome Measures  ICMJE
 (submitted: May 14, 2015)
To evaluate the effect of anifrolumab compared to placebo on disease activity as measured by the difference in the proportion of subjects who achieve an SLE Responder Index of ≥4 (SRI[4]) at Week 52 [ Time Frame: Week 52 ]
Composite endpoint SRI(4), defined by the following criteria:
  • Reduction from baseline of ≥4 points in the SLEDAI-2K and
  • No new organ system affected as defined by 1 or more British Isles Lupus Assessment Group (BILAG) 2004 A or 2 or more BILAG-2004 B items compared to baseline using BILAG-2004 and
  • No worsening from baseline in subjects' lupus disease activity defined by an increase ≥0.30 points on a 3 point Physician's Global Assessment (PGA) visual analogue scale (VAS) and
  • No discontinuation of investigational product or use of restricted medications beyond the protocol allowed threshold before assessment
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 5, 2020)
  • Number of Participants Who Achieved the British Isles Lupus Assessment Group Based Composite Lupus Assessment (BICLA) Response at Week 52 in the IFN Test-High Sub-group [ Time Frame: Baseline; Week 52 ]
    Composite endpoint BICLA, was defined by meeting all of the following criteria:
    • Reduction of all baseline British Isles Lupus Assessment Group (BILAG)-2004 A to B/C/D and baseline BILAG-2004 B to C/D, and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B
    • No worsening from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), where worsening is defined as an increase from baseline to >0 points in SLEDAI-2K
    • No worsening from baseline in participants' lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point Physician's Global Assessment (PGA) visual analogue scale (VAS)
    • No discontinuation of investigational product
    • No use of restricted medications beyond the protocol allowed threshold before assessment
  • Number of Participants Who Achieved and Maintained an Oral Corticosteroids (OCS) Dose of ≤7.5 mg/Day at Week 52 in the Sub-Group of Participants With Baseline OCS ≥10 mg/Day [ Time Frame: Week 40; Week 52 ]
    Maintained OCS reduction was defined by meeting all of the following criteria:
    • Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40
    • Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to Week 52
    • No discontinuation of investigational product
    • No use of restricted medications beyond the protocol allowed threshold before assessment
  • Number of Participants With a ≥50% Reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score at Week 12 in The Sub-Group of Participants With Baseline CLASI Activity Score of ≥10 [ Time Frame: Baseline; Week 12 ]
    50% reduction in CLASI activity score compared to baseline was defined by meeting all of the following criteria:
    • Achieve ≥50% reduction of CLASI activity score at Week 12 compared to baseline
    • No discontinuation of investigational product
    • No use of restricted medications beyond the protocol allowed threshold before assessment
  • Number of Participants With ≥50% Reduction in Joint Counts at Week 52 in The Sub-group of Participants With ≥6 Swollen and ≥6 Tender Joints at Baseline [ Time Frame: Baseline; Week 52 ]
    50% reduction in the number of swollen and tender joints compared to baseline was defined by meeting all of the following criteria:
    • Achieve ≥50% reduction from baseline in the number of swollen and tender joints, separately
    • No discontinuation of investigational product
    • No use of restricted medications beyond the protocol allowed threshold before assessment
  • Annualised Flare Rate Through 52 Weeks [ Time Frame: Baseline to Week 52 ]
    A flare was defined as either 1 or more new British Isle Lupus Assessment Group (BILAG-2004) A or 2 or more new BILAG-2004 B items compared to the previous visit. The occurrence of a new flare was checked for each available visit versus the previous available visit up to Week 52. If no new flares occurred, the number of flares was set to 0. Otherwise all flares were counted leading to the maximum number of flares of 13. The annualized flare rate was calculated as the number of flares divided by the flare exposure time in days multiplied with 365.25 (1 year). The flare exposure time is the time up to Week 52 (date of BILAG-2004 assessment at Week 52) or up to the date of last available BILAG-2004 assessment.
  • Number of Participants With One or More Adverse Events (AEs) [ Time Frame: Baseline to end of study (Maximum of 60 weeks) ]
    An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. AEs were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE). The reported value is inclusive of serious and non-serious AEs.
  • Number of Participants With One or More Adverse Events of Special Interest (AESIs) [ Time Frame: Baseline to end of study (Maximum of 60 weeks) ]
    An AESI is an adverse event (AE) of scientific and medical concern specific to understanding biologics. An AESI may be serious or non-serious. AESI are serious infections, including non-opportunistic serious infections, opportunistic infections, anaphylaxis, malignancy, herpes zoster, tuberculosis (TB) (including latent TB), influenza, vasculitis (non-systemic lupus erythematosus [SLE]), and major adverse cardiovascular events (MACE) (including stroke, myocardial infarction [MI], or cardiovascular death). AESIs were collected throughout the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).
  • Number of Participants With a Potentially Clinically Important Change From Baseline in Vital Sign Measurements [ Time Frame: Baseline to end of study (Maximum of 60 weeks) ]
    Vital sign measurements included oral temperature, blood pressure (BP), pulse rate, and respiratory rate. Vital signs were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).
  • Number of Participants With a Potentially Clinically Important Change From Baseline in Clinical Laboratory Tests [ Time Frame: Baseline to end of study (Maximum of 60 weeks) ]
    Clinical laboratory tests were analyzed in a central clinical laboratory and included hematology, serum chemistry and urinalysis tests. Laboratory values were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).
Original Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2015)
  • To evaluate the effect of anifrolumab compared to placebo on the proportion of subjects with SRI(4) at Week 52 in the IFN test-high sub-group [ Time Frame: Week 52 ]
    Composite endpoint SRI(4), defined by the following criteria:
    • Reduction from baseline of ≥4 points in the SLEDAI-2K and
    • No new organ system affected as defined by 1 or more British Isles Lupus Assessment Group (BILAG) 2004 A or 2 or more BILAG-2004 B items compared to baseline using BILAG-2004 and
    • No worsening from baseline in subjects' lupus disease activity defined by an increase ≥0.30 points on a 3 point Physician's Global Assessment (PGA) visual analogue scale (VAS) and
    • No discontinuation of investigational product or use of restricted medications beyond the protocol allowed threshold before assessment
  • To evaluate the effect of anifrolumab compared to placebo on the proportion of subjects who achieve an OCS dose ≤7.5 mg/day at Week 40, which is maintained through Week 52 in the sub-group of subjects with baseline OCS ≥10 mg/day [ Time Frame: Week 52 ]
    Maintained OCS reduction defined by the following criteria:
    • Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40 and
    • Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to Week 52 and
    • No discontinuation of investigational product or use of restricted medications beyond the protocol allowed threshold before assessment
  • To evaluate the effect of anifrolumab compared to placebo on the proportion of subjects with a ≥50% reduction in CLASI activity score at Week 12 in the sub-group of subjects with baseline CLASI activity score ≥10 [ Time Frame: Week 12 ]
    50% reduction in CLASI activity score compared to baseline defined by the following criteria:
    • Achieve ≥50% reduction of CLASI activity score at Week 12 compared to baseline and
    • No discontinuation of investigational product or use of restricted medications beyond the protocol allowed threshold before assessment
  • To evaluate the effect of anifrolumab compared to placebo on the proportion of subjects with SRI(4) at Week 24 [ Time Frame: Week 24 ]
    Composite endpoint SRI(4), defined by the following criteria:
    • Reduction from baseline of ≥4 points in the SLEDAI-2K and
    • No new organ system affected as defined by 1 or more British Isles Lupus Assessment Group (BILAG) 2004 A or 2 or more BILAG-2004 B items compared to baseline using BILAG-2004 and
    • No worsening from baseline in subjects' lupus disease activity defined by an increase ≥0.30 points on a 3 point Physician's Global Assessment (PGA) visual analogue scale (VAS) and
    • No discontinuation of investigational product or use of restricted medications beyond the protocol allowed threshold before assessment
  • To evaluate the effect of anifrolumab compared to placebo on the annualised flare rate through 52 weeks [ Time Frame: Week 0-52 ]
    Annualised flare rate with flare defined as either 1 or more new BILAG 2004 A or 2 or more new BILAG 2004 B items compared to the previous visit
  • To evaluate the safety and tolerability of anifrolumab [ Time Frame: Week 0-52 ]
    Adverse events (AEs) (including adverse events of special interest [AESIs]), vital signs, physical examination, 12-lead electrocardiograms, modified SLEDAI Flare Index based flares, clinical laboratory tests (haematology, clinical chemistry, urinalysis), Columbia Suicide Severity Rating Scale, and Personal Health Questionnaire Depression Scale-8
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus
Official Title  ICMJE A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects With Active Systemic Lupus Erythematosus
Brief Summary The purpose of this study is to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab versus placebo in adult participants with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE).
Detailed Description

This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab versus placebo in participants with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. Participants must be taking either 1 or any combination of the following: oral corticosteroids (OCS), antimalarial, and/or immunosuppressants. The study will be performed in adult participants aged 18 to 70 years of age.

Approximately 360 participants receiving SOC treatment will be randomised in a 1:1 ratio to receive a fixed intravenous dose of anifrolumab 300 mg or placebo every 4 weeks for a total of 13 doses (Week 0 to Week 48), with the primary endpoint evaluated at the Week 52 visit. Investigational product will be administered as an intravenous infusion (IV) via an infusion pump over a minimum of 30 minutes, every 4 weeks.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Active Systemic Lupus Erythematosus
Intervention  ICMJE
  • Biological: Anifrolumab
    Intravenous infusion (IV)
  • Drug: Placebo
    Intravenous infusion (IV)
Study Arms  ICMJE
  • Experimental: Anifrolumab
    Anifrolumab 300 mg intravenous infusion (IV) administered every 4 weeks for a total of 13 doses.
    Intervention: Biological: Anifrolumab
  • Placebo Comparator: Placebo
    Placebo intravenous infusion (IV) administered every 4 weeks for a total of 13 doses.
    Intervention: Drug: Placebo
Publications * Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C, Bae SC, Brohawn PZ, Pineda L, Berglind A, Tummala R; TULIP-2 Trial Investigators. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020 Jan 16;382(3):211-221. doi: 10.1056/NEJMoa1912196. Epub 2019 Dec 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 20, 2017)
373
Original Estimated Enrollment  ICMJE
 (submitted: May 14, 2015)
360
Actual Study Completion Date  ICMJE September 27, 2018
Actual Primary Completion Date September 27, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Aged 18 through 70 years at the time of screening
  2. Diagnosis of paediatric or adult SLE with a diagnosis of SLE according to the ACR 1982 revised criteria ≥24 weeks prior to signing the Informed Consent form (ICF)
  3. Currently receiving at least 1 of the following:

    1. Where prednisone is the single standard of care medication (ie, the subject is not concurrently receiving any medication listed in inclusion criterion 3(c)), a dose of oral prednisone ≥7.5 mg/day but ≤40 mg/day (or prednisone equivalent) for a minimum of 8 weeks prior to Day 1. In addition, the dose of oral prednisone or prednisone equivalent the subject is taking must be stable for a minimum of 2 weeks prior to randomisation
    2. Where prednisone is not the single standard of care medication (ie, the subject is concurrently receiving at least one medication listed in inclusion criterion 3(c), a dose of oral prednisone (≤40 mg/day) (or prednisone equivalent) for a minimum of 2 weeks prior to signing of the ICF. In addition, the dose of oral prednisone or prednisone equivalent the subject is taking must be stable for a minimum of 2 weeks prior to randomisation.
    3. Any of the following medications administered for a minimum of 12 weeks prior to signing the informed consent, and at a stable dose for a minimum of 8 weeks prior to signing the informed consent and through Day 1:

    (i) Azathioprine ≤200 mg/day (ii) Antimalarial (eg, chloroquine, hydroxychloroquine, quinacrine) (iii) Mycophenolate mofetil ≤2 g/day or mycophenolic acid ≤1.44 g/day (iv) Oral, subcutaneous (SC), or intramuscular methotrexate ≤25 mg/week (v) Mizoribine ≤150 mg/day

  4. Fulfils at least 4 of the 11 ACR modified 1982 classification criteria for SLE, at least 1 of which must be:

    1. Positive antinuclear antibody (ANA) test at screening by immunofluorescent assay (IFA) at the central laboratory with titre ≥1:80; OR
    2. Anti-dsDNA antibodies at screening elevated to above normal (including indeterminate), as per the central laboratory; OR
    3. Anti-Smith (anti-Sm) antibody at screening elevated to above normal as per the central laboratory
  5. At Screening, Disease Activity Adjudication Group confirmation of:

    SLEDAI-2K Criteria: SLEDAI-2K score ≥6 points and "Clinical" SLEDAI-2K score ≥4 points. The "Clinical" SLEDAI-2K is the SLEDAI-2K assessment score without the inclusion of points attributable to any urine or laboratory results including immunologic measures.

  6. Must not have active or latent TB on either chest radiograph or by quantiferon gold test
  7. Day 1 "Clinical" SLEDAI-2K score ≥4 points
  8. OCS dose stable for at least 2 weeks prior to randomisation
  9. Stable SLE SOC treatment at the time of randomisation
  10. Women of child-bearing potential must have a negative serum β-hCG test at and negative urine pregnancy test at randomisation prior to administration of investigational product

Exclusion Criteria:

  1. Receipt of any investigational product (small molecule or biologic agent) within 4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater
  2. Receipt of any of the following:

    (a) Intra-articular, intramuscular or IV glucocorticosteroids within 6 weeks prior to Day 1

  3. History of, or current diagnosis of, a clinically significant non SLE-related vasculitis syndrome.
  4. Active severe or unstable neuropsychiatric SLE
  5. Active severe SLE-driven renal disease
  6. Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or any history of overlap syndromes of SLE or SSc.
  7. History of, or current, inflammatory joint or skin disease other than SLE
  8. History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids for more than 2 weeks within the last 24 weeks prior to signing the ICF
  9. 26.27. Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the subject to infection, or a positive result for human immunodeficiency virus (HIV) infection confirmed by central laboratory at screening. Subjects refusing HIV testing during the screening period will not be eligible for study participation
  10. Confirmed positive test for hepatitis B or hepatitis C
  11. Any severe herpes infection at any time prior to Week 0 (Day 1)
  12. Opportunistic infection requiring hospitalisation or intravenous antimicrobial treatment within 3 years prior to randomization
  13. History of cancer, apart from:

    1. Squamous or basal cell carcinoma of the skin that has been successfully treated
    2. Cervical cancer in situ that has been successfully treated
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Belgium,   Brazil,   Bulgaria,   Canada,   France,   Germany,   Japan,   Korea, Republic of,   Lithuania,   Mexico,   Russian Federation,   South Africa,   Spain,   United States
Removed Location Countries Czech Republic,   Czechia,   Singapore
 
Administrative Information
NCT Number  ICMJE NCT02446899
Other Study ID Numbers  ICMJE D3461C00004
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE PRA Health Sciences
Investigators  ICMJE
Study Director: Lilia Pineda, MD Medical Science Director
PRS Account AstraZeneca
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP