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

NCT02446912 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: D3461C00005
• Study Type: interventional
• Target: 460
• Locations: 18 countries
• Sites: 145

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).

Conditions

Active Systemic Lupus Erythematosus

Keywords

Active Systemic Lupus Erythematosus

Outcome Measures

Primary Outcomes (1)

• Number of Participants Who Achieved a Systemic Lupus Erythematosus (SLE) Responder Index ≥4 (SRI[4]) at Week 52 (Original Analysis With Restricted Medication Rules)

  SRI(4) was defined as meeting all of the following criteria: Reduction from baseline of ≥4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) No new organ systems affected, defined by 1 or more British Isles Lupus Assessment Group (BILAG-2004) A or 2 or more BILAG-2004 B items No worsening from baseline in participants lupus disease activity. Worsening was defined as an increase of ≥0.30 points on a 3-point Physician's Global Assessment (PGA) visual analogue scale (VAS) No discontinuation of investigational product and no use of restricted medications beyond the pre-specified analysis threshold.

  Week 52

Secondary Outcomes (15)

• 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)

  Week 52

• 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)

  Week 52

• 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)

  Week 12

• 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)

  Week 24

• Annualized Flare Rate

  Baseline to Week 52

Study Arms (3)

Anifrolumab - higher dose

EXPERIMENTAL

Anifrolumab

Biological: Anifrolumab

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Anifrolumab - lower dose

EXPERIMENTAL

Anifrolumab

Biological: Anifrolumab

Interventions

Anifrolumab BIOLOGICAL

Anifrolumab IV administration every 4 weeks from Week 0 to Week 48 for a total of 13 doses

Anifrolumab - higher dose; Anifrolumab - lower dose

Placebo DRUG

Placebo IV administration every 4 weeks from Week 0 to Week 48

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 18 through 70 years at the time of screening
• 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)
• Currently receiving at least 1 of the following:
• 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
• Fulfils at least 4 of the 11 ACR modified 1982 classification criteria for SLE, at least 1 of which must be:
• Positive antinuclear antibody (ANA) test at screening by immunofluorescent assay (IFA) at the central laboratory with titre ≥1:80; OR
• Anti-dsDNA antibodies at screening elevated to above normal (including indeterminante), as per the central laboratory; OR
• Anti-Smith (anti-Sm) antibody at screening elevated to above normal as per the central laboratory.
• At Screening, Disease Activity Adjudication Group confirmation of:
• Must not have active or latent TB on either chest radiograph or by quantiferon gold test
• Day 1 "Clinical" SLEDAI-2K score ≥4 points
• OCS dose stable for at least 2 weeks prior to randomisation
• Stable SLE SOC treatment at the time of randomisation
• 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

You may not qualify if:

• 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
• Receipt of any of the following:
• (a) Intra-articular, intramuscular or IV glucocorticosteroids within 6 weeks prior to Day 1
• History of, or current diagnosis of, a clinically significant non SLE-related vasculitis syndrome.
• Active severe or unstable neuropsychiatric SLE
• Active severe SLE-driven renal disease
• Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or any history of overlap syndromes of SLE or SSc.
• History of, or current, inflammatory joint or skin disease other than SLE
• 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
• 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
• Confirmed positive test for hepatitis B or hepatitis C
• Any severe herpes infection at any time prior to Week 0 (Day 1)
• Opportunistic infection requiring hospitalisation or intravenous antimicrobial treatment within 3 years prior to randomization
• History of cancer, apart from:
• Squamous or basal cell carcinoma of the skin that has been successfully treated

Sponsors & Collaborators

• AstraZeneca: lead
• PRA Health Sciences: collaborator

Study Sites (145)

Research Site

Birmingham, Alabama, 35233, United States

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El Cajon, California, 91942-3191, United States

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La Jolla, California, 92037-0706, United States

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Los Alamitos, California, 90720, United States

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Thousand Oaks, California, 91360, United States

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Aurora, Colorado, 80045, United States

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Aventura, Florida, 33180, United States

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Miami, Florida, 33136, United States

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Orlando, Florida, 32804, United States

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Orlando, Florida, 32806, United States

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Ormond Beach, Florida, 32174, United States

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Plantation, Florida, 33324, United States

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Tampa, Florida, 33614, United States

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Vero Beach, Florida, 32960, United States

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Decatur, Georgia, 30033, United States

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Lawrenceville, Georgia, 30046, United States

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Marietta, Georgia, 30060, United States

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Boise, Idaho, 83712, United States

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Idaho Falls, Idaho, 83404, United States

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Baton Rouge, Louisiana, 70809, United States

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Hagerstown, Maryland, 21502, United States

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Hagerstown, Maryland, 21740, United States

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Grand Rapids, Michigan, 49546, United States

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Minneapolis, Minnesota, 55455-0341, United States

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Nashua, New Hampshire, 03060, United States

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Freehold, New Jersey, 07728, United States

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Great Neck, New York, 11021, United States

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New Hyde Park, New York, 11042, United States

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Charlotte, North Carolina, 28204, United States

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Charlotte, North Carolina, 28210, United States

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Raleigh, North Carolina, 27617, United States

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Cleveland, Ohio, 44109, United States

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Middleburg Heights, Ohio, 44130, United States

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Oklahoma City, Oklahoma, 73101, United States

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Tulsa, Oklahoma, 74104, United States

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Philadelphia, Pennsylvania, 19140, United States

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Pittsburgh, Pennsylvania, 15224, United States

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Wyomissing, Pennsylvania, 19610, United States

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Charleston, South Carolina, 29406, United States

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Charleston, South Carolina, 29407, United States

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Charleston, South Carolina, 29425, United States

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Jackson, Tennessee, 38305, United States

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Memphis, Tennessee, 38119, United States

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Amarillo, Texas, 79124, United States

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Austin, Texas, 78731, United States

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Austin, Texas, 78745, United States

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Dallas, Texas, 75231, United States

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Houston, Texas, 77074, United States

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Houston, Texas, 77099, United States

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Mesquite, Texas, 75150, United States

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San Antonio, Texas, 78232, United States

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Glendale, Wisconsin, 53217, United States

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Córdoba, X5004AUL, Argentina

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San Miguel de Tucumán, T4000AXL, Argentina

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Fitzroy, 3065, Australia

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Kogarah, 2217, Australia

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St Leonards, 2065, Australia

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Belo Horizonte, 30150-221, Brazil

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Juiz de Fora, 36010-570, Brazil

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Porto Alegre, 90560-030, Brazil

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Salvador, 40150-150, Brazil

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Osorno, 5311092, Chile

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Santiago, 8320000, Chile

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Viña del Mar, 2520997, Chile

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Armenia, 630004, Colombia

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Barranquilla, 0, Colombia

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Bogotá, 110221, Colombia

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Bogotá, 111211, Colombia

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Bucaramanga, 680003, Colombia

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Medellín, 050021, Colombia

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Berlin, 10117, Germany

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Cologne, 50937, Germany

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Dessau-RoBlau, 06847, Germany

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Frankfurt am Main, 60528, Germany

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Göttingen, 37075, Germany

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Kirchheim, 73230, Germany

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Budapest, 1097, Hungary

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Debrecen, 4032, Hungary

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Szeged, 6725, Hungary

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Zalaegerszeg, 8900, Hungary

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Haifa, 31048, Israel

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Haifa, 3109601, Israel

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Jerusalem, 9122001, Israel

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Kfar Saba, 49281, Israel

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Petah Tikva, 49100, Israel

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Tel Aviv, 64239, Israel

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Milan, 20132, Italy

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Milan, 20157, Italy

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Padua, 35128, Italy

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Hamilton, 3204, New Zealand

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Wellington, 6021, New Zealand

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Arequipa, 54, Peru

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Lima, 15023, Peru

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Lima, 15033, Peru

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Lima, 15046, Peru

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Lima, 15073, Peru

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Lima, LIMA 01, Peru

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Lima, LIMA 31, Peru

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Bialystok, 15-297, Poland

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Bydgoszcz, 85-168, Poland

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Elblag, 82-300, Poland

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Krakow, 31-011, Poland

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Lublin, 20-582, Poland

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Nadarzyn, 05-830, Poland

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Poznan, 60-773, Poland

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Poznan, 61-397, Poland

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Sosnowiec, 41-200, Poland

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Starachowice, 27-200, Poland

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Szczecin, 71-252, Poland

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Ustroń, 43-450, Poland

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Warsaw, 02-118, Poland

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Warsaw, 50-088, Poland

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Brasov, 500283, Romania

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Bucharest, 010584, Romania

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Bucharest, 011172, Romania

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Bucharest, 020475, Romania

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Cluj-Napoca, 400006, Romania

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Galati, 800578, Romania

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Tg Mures, 540136, Romania

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Daejeon, 301-721, South Korea

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Gwangju, 61469, South Korea

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Jeonju, 54907, South Korea

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Seoul, 03080, South Korea

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Seoul, 150-713, South Korea

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Suwon, 61469, South Korea

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Kaohsiung Hsien, 83342, Taiwan

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Taichung, 404, Taiwan

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Taichung, 40705, Taiwan

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Taipei, 10002, Taiwan

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Kiev, 03680, Ukraine

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Kyiv, 01601, Ukraine

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Kyiv, 02002, Ukraine

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Lviv, 79010, Ukraine

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Lviv, 79011, Ukraine

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Ternopil, 46002, Ukraine

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Uzhhorod, 88000, Ukraine

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Vinnytsia, 21018, Ukraine

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Zaporizhzhia, 69600, Ukraine

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Brighton, BN2 5BE, United Kingdom

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Doncaster, DN2 5LT, United Kingdom

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Leeds, LS7 4SA, United Kingdom

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London, SE1 2PR, United Kingdom

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Manchester, M13 9WL, United Kingdom

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Romford, RM7 0AG, United Kingdom

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Staffordshire, WS11 5XY, United Kingdom

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Related Publications (10)

• Furie RA, Morand EF, Bruce IN, Manzi S, Kalunian KC, Vital EM, Lawrence Ford T, Gupta R, Hiepe F, Santiago M, Brohawn PZ, Berglind A, Tummala R; TULIP-1 study investigators. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019 Dec;1(4):e208-e219. doi: 10.1016/S2665-9913(19)30076-1. Epub 2019 Nov 11.

  PMID: 38229377 DERIVED

• Morand EF, Abreu G, Furie RA, Golder V, Tummala R. Lupus low disease activity state attainment in the phase 3 TULIP trials of anifrolumab in active systemic lupus erythematosus. Ann Rheum Dis. 2023 May;82(5):639-645. doi: 10.1136/ard-2022-222748. Epub 2023 Jan 23.

  PMID: 36690388 DERIVED

• 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.

  PMID: 36018235 DERIVED

• 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.

  PMID: 35580976 DERIVED

• 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.

  PMID: 35338035 DERIVED

• 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.

  PMID: 35157371 DERIVED

• 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.

  PMID: 34528084 DERIVED

• 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.

  PMID: 33977796 DERIVED

• 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.

  PMID: 33913260 DERIVED

• 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.

  PMID: 33687069 DERIVED

Related Links

• CSP redacted.
• SAP redacted.

MeSH Terms

Interventions

anifrolumab

Results Point of Contact

• Title: Global Clinical Leader
• Organization: AstraZeneca AB

ClinicalTrialTransparency@astrazeneca.com

+46317761000

Study Officials

• Herbert Hutman, MD

  Medical Science Director

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2015
• First Posted: May 18, 2015
• Study Start: June 9, 2015
• Primary Completion: July 17, 2018
• Study Completion: July 17, 2018
• Last Updated: January 12, 2023
• Results First Posted: December 5, 2019

Record last verified: 2022-12

Locations

UA (9); CL (3); CO (6); TW (4); NZ (2); US (52); DE (6); HU (4); AU (3); AR (2); IT (3); BR (4); PL (14); RO (7); IL (6); GB (7); PE (7); KR (6)