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

NCT ID: NCT02446899

Last Updated: 2023-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 373 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-07-09
• Study Completion Date: 2018-09-27

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.

Conditions

Active Systemic Lupus Erythematosus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Anifrolumab

Anifrolumab 300 mg intravenous infusion (IV) administered every 4 weeks for a total of 13 doses.

Group Type: EXPERIMENTAL

Anifrolumab

Intervention Type: BIOLOGICAL

Intravenous infusion (IV)

Placebo

Placebo intravenous infusion (IV) administered every 4 weeks for a total of 13 doses.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Intravenous infusion (IV)

Interventions

Anifrolumab

Intravenous infusion (IV)

Intervention Type: BIOLOGICAL

Placebo

Intravenous infusion (IV)

Intervention Type: DRUG

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 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

PRA Health Sciences

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lilia Pineda, MD

Role: STUDY_DIRECTOR

Medical Science Director

Locations

Research Site

Covina, California, United States

Research Site

Hemet, California, United States

Research Site

Los Angeles, California, United States

Research Site

San Leandro, California, United States

Research Site

Torrance, California, United States

Research Site

Upland, California, United States

Research Site

Denver, Colorado, United States

Research Site

Bridgeport, Connecticut, United States

Research Site

Bridgeport, Connecticut, United States

Research Site

Brandon, Florida, United States

Research Site

Orlando, Florida, United States

Research Site

Palm Harbor, Florida, United States

Research Site

Tamarac, Florida, United States

Research Site

Tampa, Florida, United States

Research Site

Atlanta, Georgia, United States

Research Site

Boston, Massachusetts, United States

Research Site

Ann Arbor, Michigan, United States

Research Site

Lincoln, Nebraska, United States

Research Site

Las Cruces, New Mexico, United States

Research Site

Brooklyn, New York, United States

Research Site

New York, New York, United States

Research Site

New York, New York, United States

Research Site

New York, New York, United States

Research Site

Greenville, North Carolina, United States

Research Site

Oklahoma City, Oklahoma, United States

Research Site

Duncansville, Pennsylvania, United States

Research Site

Pittsburgh, Pennsylvania, United States

Research Site

Memphis, Tennessee, United States

Research Site

Dallas, Texas, United States

Research Site

Houston, Texas, United States

Research Site

Houston, Texas, United States

Research Site

Stafford, Texas, United States

Research Site

Arlington, Virginia, United States

Research Site

Seattle, Washington, United States

Research Site

Spokane, Washington, United States

Research Site

Buenos Aires, , Argentina

Research Site

Mendoza, , Argentina

Research Site

Quilmes, , Argentina

Research Site

Brussels, , Belgium

Research Site

Leuven, , Belgium

Research Site

Liège, , Belgium

Research Site

Merksem, , Belgium

Research Site

Goiânia, , Brazil

Research Site

Juiz de Fora, , Brazil

Research Site

São Paulo, , Brazil

Research Site

São Paulo, , Brazil

Research Site

São Paulo, , Brazil

Research Site

Plovdiv, , Bulgaria

Research Site

Plovdiv, , Bulgaria

Research Site

Hamilton, Ontario, Canada

Research Site

Rimouski, Quebec, Canada

Research Site

Bordeaux, , France

Research Site

Lille, , France

Research Site

Montpellier, , France

Research Site

Paris, , France

Research Site

Paris, , France

Research Site

Pessac, , France

Research Site

Toulouse, , France

Research Site

Berlin, , Germany

Research Site

Hamburg, , Germany

Research Site

Jena, , Germany

Research Site

Mainz, , Germany

Research Site

München, , Germany

Research Site

Chiba, , Japan

Research Site

Chūōku, , Japan

Research Site

Fukuoka, , Japan

Research Site

Fukuoka, , Japan

Research Site

Hiroshima, , Japan

Research Site

Kitakyushu-shi, , Japan

Research Site

Kurashiki-shi, , Japan

Research Site

Meguro-ku, , Japan

Research Site

Meguro-ku, , Japan

Research Site

Nagasaki, , Japan

Research Site

Nagoya, , Japan

Research Site

Omura-shi, , Japan

Research Site

Sapporo, , Japan

Research Site

Sasebo-shi, , Japan

Research Site

Sendai, , Japan

Research Site

Shinjuku-ku, , Japan

Research Site

Tsukuba, , Japan

Research Site

Kaunas, , Lithuania

Research Site

Klaipėda, , Lithuania

Research Site

Chihuahua City, , Mexico

Research Site

León, , Mexico

Research Site

Mexico City, , Mexico

Research Site

Mérida, , Mexico

Research Site

México, , Mexico

Research Site

Morelia, , Mexico

Research Site

San Luis Potosí City, , Mexico

Research Site

Kemerovo, , Russia

Research Site

Petrozavodsk, , Russia

Research Site

Smolensk, , Russia

Research Site

Tolyatti, , Russia

Research Site

Vladimir, , Russia

Research Site

Yaroslavl, , Russia

Research Site

Cape Town, , South Africa

Research Site

Johannesburg, , South Africa

Research Site

Johannesburg, , South Africa

Research Site

Stellenbosch, , South Africa

Research Site

Jeju City, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Suwon, , South Korea

Research Site

Barcelona, , Spain

Research Site

Getafe, , Spain

Research Site

Las Palmas de Gran Canaria, , Spain

Research Site

Madrid, , Spain

Research Site

Madrid, , Spain

Research Site

Mérida, , Spain

Research Site

Santiago de Compostela, , Spain

Research Site

Servilla, , Spain

Research Site

Vigo, , Spain

Countries

United States; Argentina; Belgium; Brazil; Bulgaria; Canada; France; Germany; Japan; Lithuania; Mexico; Russia; South Africa; South Korea; Spain

References

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.

Reference Type: DERIVED

PMID: 36690388 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36018235 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35580976 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35338035 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35157371 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34528084 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33977796 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33913260 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33687069 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31851795 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

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