Clinical trial NCT02446912: Efficacy and Safety of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus
Official title: A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Study Evaluating the Efficacy and Safety of Two Doses of Anifrolumab in Adult Subjects With Active Systemic Lupus Erythematosus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Active Systemic Lupus Erythematosus
Keywords: Active Systemic Lupus Erythematosus
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: PRA Health Sciences
First posted: 2015-05-18
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of an intravenous treatment regimen of two doses of anifrolumab versus placebo in adult subjects 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 two doses of anifrolumab versus placebo in subjects with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. The study will be performed in adult subjects aged 18 to 70 years of age.

Eligibility criteria: 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 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 indeterminante), 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 and negative urine pregnancy test at randomisation (Day 1) 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. 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

Primary outcomes:
measure: Number of Participants Who Achieved a Systemic Lupus Erythematosus (SLE) Responder Index ≥4 (SRI[4]) at Week 52 (Original Analysis With Restricted Medication Rules)
timeFrame: Week 52
Secondary outcomes:
measure: Number of Participants Who Achieved a Systemic Lupus Erythematosus (SLE) Responder Index of ≥4 at Week 52 in the Interferon (IFN) Test-High Sub-Group (Original Analysis With Restricted Medication Rules)
timeFrame: Week 52
measure: Number of Participants Who Achieved and Maintained an Oral Corticosteroid (OCS) Dose of ≤7.5 mg/Day in the Sub-group of Participants With Baseline OCS ≥10 mg/Day (Original Analysis With Restricted Medication Rules)
timeFrame: Week 52
measure: Number of Participants With a ≥50% Reduction in CLASI Activity Score at Week 12 in the Sub-group of Participants With Baseline CLASI Activity Score ≥10 (Original Analysis With Restricted Medication Rules)
timeFrame: Week 12
measure: Number of Participants Who Achieved a Systemic Lupus Erythematosus (SLE) Responder Index of ≥4 (SRI[4]) at Week 24 (Original Analysis With Restricted Medication Rules)
timeFrame: Week 24
measure: Annualized Flare Rate
timeFrame: Baseline to Week 52
measure: Number of Participants Who Met the Criteria for British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) Response (Original Analysis With Restricted Medication Rules)
timeFrame: Week 52
measure: Number of Participants Reporting One or More Adverse Events (AE)
timeFrame: Baseline to End of Trial (Maximum of 60 weeks)
measure: Number of Participants Reporting One or More Adverse Events of Special Interest (AESI)
timeFrame: Baseline to End of Trial (Maximum of 60 weeks)
measure: Number of Participants With Markedly Abnormal Vital Signs
timeFrame: Baseline to End of Trial (Maximum of 60 weeks)
measure: Number of Participants With Markedly Abnormal Physical Examinations
timeFrame: Baseline to End of Trial (Maximum of 60 weeks)
measure: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Scores
timeFrame: Baseline to Week 52
measure: Number of Participants With Mild To Moderate Lupus Flare Evaluated by Modified Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI Flare Index
timeFrame: Baseline to End of Trial (Maximum of 60 weeks)
measure: Number of Participants With Markedly Abnormal Laboratory Tests
timeFrame: Baseline to End of Trial (Maximum of 60 weeks)
measure: Number of Participants With Suicidal Ideation or Behaviour Assessed Via the Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline to Week 52
measure: Change From Baseline in Personal Health Questionnaire Depression Scale-8 (PHQ-8) Score
timeFrame: Baseline to Week 52
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site
state: Alabama
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state: California
city: La Jolla
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state: California
city: Los Alamitos
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state: California
city: Thousand Oaks
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state: California
city: Aurora
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state: Colorado
city: Aventura
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state: Florida
city: Miami
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state: Florida
city: Orlando
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city: Orlando
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city: Ormond Beach
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city: Plantation
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state: Florida
city: Vero Beach
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state: Florida
city: Decatur
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state: Georgia
city: Lawrenceville
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state: Georgia
city: Marietta
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state: Georgia
city: Boise
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state: Idaho
city: Idaho Falls
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state: Idaho
city: Baton Rouge
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state: Louisiana
city: Hagerstown
country: United States
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state: Maryland
city: Hagerstown
country: United States
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state: Maryland
city: Grand Rapids
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state: Michigan
city: Minneapolis
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state: Minnesota
city: Nashua
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city: Freehold
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state: New Jersey
city: Great Neck
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state: New York
city: New Hyde Park
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state: New York
city: Charlotte
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state: North Carolina
city: Charlotte
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city: Raleigh
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city: Middleburg Heights
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city: Charleston
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city: Charleston
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city: Belo Horizonte
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city: Salvador
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city: Osorno
country: Chile
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city: Santiago
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city: Vina del Mar
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city: Armenia
country: Colombia
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city: Medellin
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city: Berlin
country: Germany
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city: Dessau-RoBlau
country: Germany
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city: Frankfurt am Main
country: Germany
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city: Göttingen
country: Germany
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city: Kirchheim
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city: Köln
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city: Budapest
country: Hungary
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city: Debrecen
country: Hungary
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city: Szeged
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city: Zalaegerszeg
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city: Haifa
country: Israel
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city: Haifa
country: Israel
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city: Jerusalem
country: Israel
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city: Kfar Saba
country: Israel
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city: Petach-Tikva
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
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city: Milano
country: Italy
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city: Milano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Daejeon
country: Korea, Republic of
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city: Gwangju
country: Korea, Republic of
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city: Jeonju-si
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Suwon-si
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city: Hamilton
country: New Zealand
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city: Wellington
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city: Arequipa
country: Peru
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city: Lima
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city: Lima
country: Peru
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city: Białystok
country: Poland
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city: Bydgoszcz
country: Poland
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city: Elblag
country: Poland
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city: Kraków
country: Poland
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city: Lublin
country: Poland
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city: Nadarzyn
country: Poland
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city: Poznań
country: Poland
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city: Poznań
country: Poland
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city: Sosnowiec
country: Poland
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city: Starachowice
country: Poland
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city: Szczecin
country: Poland
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city: Ustron
country: Poland
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city: Warszawa
country: Poland
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city: Warszawa
country: Poland
facility: Research Site
city: Brasov
country: Romania
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Cluj Napoca
country: Romania
facility: Research Site
city: Galati
country: Romania
facility: Research Site
city: Tg Mures
country: Romania
facility: Research Site
city: Kaohsiung Hsien
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Kiev
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Ternopil
country: Ukraine
facility: Research Site
city: Uzhgorod
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
city: Zaporizhzhia
country: Ukraine
facility: Research Site
city: Brighton
country: United Kingdom
facility: Research Site
city: Doncaster
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Romford
country: United Kingdom
facility: Research Site
city: Staffordshire
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Medical Science Director
name: Herbert Hutman, MD
role: STUDY_DIRECTOR
References:
citation: Bruce IN, van Vollenhoven RF, Morand EF, Furie RA, Manzi S, White WB, Abreu G, Tummala R. Sustained glucocorticoid tapering in the phase 3 trials of anifrolumab: a post hoc analysis of the TULIP-1 and TULIP-2 trials. Rheumatology (Oxford). 2023 Apr 3;62(4):1526-1534. doi: 10.1093/rheumatology/keac491.
citation: Bruce IN, Furie RA, Morand EF, Manzi S, Tanaka Y, Kalunian KC, Merrill JT, Puzio P, Maho E, Kleoudis C, Albulescu M, Hultquist M, Tummala R. Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials. Ann Rheum Dis. 2022 Jul;81(7):962-969. doi: 10.1136/annrheumdis-2021-221847. Epub 2022 May 17.
citation: Vital EM, Merrill JT, Morand EF, Furie RA, Bruce IN, Tanaka Y, Manzi S, Kalunian KC, Kalyani RN, Streicher K, Abreu G, Tummala R. Anifrolumab efficacy and safety by type I interferon gene signature and clinical subgroups in patients with SLE: post hoc analysis of pooled data from two phase III trials. Ann Rheum Dis. 2022 Jul;81(7):951-961. doi: 10.1136/annrheumdis-2021-221425. Epub 2022 Mar 25.
citation: Loncharich MF, Anderson CW. Interferon Inhibition for Lupus with Anifrolumab: Critical Appraisal of the Evidence Leading to FDA Approval. ACR Open Rheumatol. 2022 Jun;4(6):486-491. doi: 10.1002/acr2.11414. Epub 2022 Feb 14.
citation: Chia YL, Zhang J, Tummala R, Rouse T, Furie RA, Morand EF. Relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2022 May 5;61(5):1900-1910. doi: 10.1093/rheumatology/keab704.
citation: Furie R, Morand EF, Askanase AD, Vital EM, Merrill JT, Kalyani RN, Abreu G, Pineda L, Tummala R. Anifrolumab reduces flare rates in patients with moderate to severe systemic lupus erythematosus. Lupus. 2021 Jul;30(8):1254-1263. doi: 10.1177/09612033211014267. Epub 2021 May 12.
citation: Furie R, Morand EF, Bruce IN, Isenberg D, van Vollenhoven R, Abreu G, Pineda L, Tummala R. What Does It Mean to Be a British Isles Lupus Assessment Group-Based Composite Lupus Assessment Responder? Post Hoc Analysis of Two Phase III Trials. Arthritis Rheumatol. 2021 Nov;73(11):2059-2068. doi: 10.1002/art.41778. Epub 2021 Sep 22.
citation: Hannon CW, McCourt C, Lima HC, Chen S, Bennett C. Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Mar 9;3(3):CD007478. doi: 10.1002/14651858.CD007478.pub2.