A Study of the Efficacy and Safety of MEDI-546 in Systemic Lupus Erythematosus

A Phase 2, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects With Systemic Lupus Erythematosus

The purpose of this study is to evaluate the efficacy and safety of MEDI-546 compared to placebo in subjects with chronic, moderately-to-severely active systemic lupus erythematosus (SLE) with an inadequate response to standard of care treatment for SLE.

Study Overview

• Status: Completed
• Conditions: Systemic Lupus Erythematosus
• Intervention / Treatment: Biological: Anifrolumab 300 mg; Biological: Anifrolumab 1000 mg; Other: Placebo

Detailed Description

This is a Phase 2, multinational, multicenter, randomized, double-blind, placebo controlled, parallel-group study to evaluate the efficacy and safety of 2 intravenous (IV) treatment regimens in adult participants with chronic, moderately-to-severely active SLE with an inadequate response to SOC SLE. The investigational product (anifrolumab or placebo) will be administered as a fixed dose every 4 weeks (28 days) for a total of 13 doses.

• Study Type: Interventional
• Enrollment (Actual): 626
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil
    • Research Site
  • Sao Paulo, Brazil
    • Research Site
• Bulgaria
  • Plovdiv, Bulgaria
    • Research Site
  • Sofia, Bulgaria
    • Research Site
• Colombia
  • Barranquilla, Colombia
    • Research Site
  • Bogota, Colombia
    • Research Site
  • Bucaramanga, Colombia
    • Research Site
  • Chia, Colombia
    • Research Site
  • Medellin, Colombia
    • Research Site
• Czech Republic
  • Brno, Czech Republic
    • Research Site
  • Praha 2, Czech Republic
    • Research Site
  • Uherske Hradiste, Czech Republic
    • Research Site
• Hungary
  • Budapest, Hungary
    • Research Site
  • Debrecen, Hungary
    • Research Site
• India
  • Dantoli-Nagpur, India
    • Research Site
  • Hyderabad, India
    • Research Site
  • Mumbai, India
    • Research Site
  • New Delhi, India
    • Research Site
  • Pune, India
    • Research Site
  • Secunderabad, India
    • Research Site
• Korea, Republic of
  • Gwangjin-gu, Korea, Republic of
    • Research Site
  • Gwangju, Korea, Republic of
    • Research Site
  • Seodaemun-gu, Korea, Republic of
    • Research Site
  • Suwon-si, Korea, Republic of
    • Research Site
• Mexico
  • Guadalajara, Mexico
    • Research Site
  • Leon, Mexico
    • Research Site
  • Mexico, Mexico
    • Research Site
  • Toluca, Mexico
    • Research Site
• Peru
  • Arequipa, Peru
    • Research Site
  • Lima, Peru
    • Research Site
• Poland
  • Bialystok, Poland
    • Research Site
  • Bydgoszcz, Poland
    • Research Site
  • Krakow, Poland
    • Research Site
  • Nadarzyn, Poland
    • Research Site
  • Poznan, Poland
    • Research Site
• Romania
  • Brasov, Romania
    • Research Site
  • Iasi, Romania
    • Research Site
  • Targu Mures, Romania
    • Research Site
• Taiwan
  • Chiayi, Taiwan
    • Research Site
  • Kaohsiung, Taiwan
    • Research Site
  • Taichung, Taiwan
    • Research Site
  • Taipei, Taiwan
    • Research Site
• Ukraine
  • Donetsk, Ukraine
    • Research Site
  • Kyiv, Ukraine
    • Research Site
  • Lugansk, Ukraine
    • Research Site
  • Lviv, Ukraine
    • Research Site
  • Ternopil, Ukraine
    • Research Site
  • Vinnitsya, Ukraine
    • Research Site
  • Vinnytsia, Ukraine
    • Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States
      • Research Site
  • California
    • La Jolla, California, United States
      • Research Site
    • La Palma, California, United States
      • Research Site
    • Long Beach, California, United States
      • Research Site
    • Los Angeles, California, United States
      • Research Site
    • Palm Desert, California, United States
      • Research Site
    • San Leandro, California, United States
      • Research Site
    • Upland, California, United States
      • Research Site
  • Florida
    • Miami, Florida, United States
      • Research Site
    • Ocala, Florida, United States
      • Research Site
    • Orlando, Florida, United States
      • Research Site
    • Palm Harbor, Florida, United States
      • Research Site
    • Tampa, Florida, United States
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States
      • Research Site
    • Decatur, Georgia, United States
      • Research Site
    • Stockbridge, Georgia, United States
      • Research Site
  • Idaho
    • Idaho Falls, Idaho, United States
      • Research Site
  • Illinois
    • Chicago, Illinois, United States
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States
      • Research Site
  • New Mexico
    • Las Cruces, New Mexico, United States
      • Research Site
  • New York
    • New York, New York, United States
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States
      • Research Site
    • Raleigh, North Carolina, United States
      • Research Site
  • Ohio
    • Columbus, Ohio, United States
      • Research Site
  • Oklahoma
    • Edmond, Oklahoma, United States
      • Research Site
    • Tulsa, Oklahoma, United States
      • Research Site
  • Tennessee
    • Memphis, Tennessee, United States
      • Research Site
  • Texas
    • Houston, Texas, United States
      • Research Site
  • Washington
    • Seattle, Washington, United States
      • Research Site
    • Spokane, Washington, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Fulfills at least 4 of the 11 American College of Rheumatology (ACR) criteria for systemic lupus erythematosus (SLE) including a positive antinuclear antibody (ANA) greater than or equal to 1:80 or elevated anti-double-stranded DNA or anti-Smith antibody at screening
• Pediatric or adult SLE with chronic disease activity for greater than or equal to 24 weeks
• Weight greater than or equal to 40 kg
• Currently receiving stable dose of oral prednisone (or equivalent) less than or equal to 40 mg/day and/or antimalarials/immunosuppressives
• Active moderate to severe SLE disease based on SLE disease activity score (SLEDAI) and British Isles Lupus Assessment Group Index (BILAG) and Physicians Global Assessment
• No evidence of cervical malignancy on Pap smear within 2 years of randomization
• Female participants must be willing to avoid pregnancy
• Negative tuberculosis (TB) test or newly positive TB test due to latent TB for which treatment must be initiated at or before randomization.

Exclusion Criteria:

• Active severe SLE-driven renal disease or unstable renal disease prior to screening
• Active severe or unstable neuropsychiatric SLE
• Clinically significant active infection including ongoing and chronic infections
• History of human immunodeficiency virus (HIV)
• Confirmed Positive tests for hepatitis B or positive test for hepatitis C
• History of severe herpes infection such as herpes encephalitis, ophthalmic herpes, disseminated herpes
• Live or attenuated vaccine within 4 weeks prior to screening
• Participants with significant hematologic abnormalities.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Anifrolumab (MEDI-546) 300 mg; Participants will receive 300 milligram (mg) anifrolumab as an intravenous infusion every 4 weeks for 48 weeks.	Biological: Anifrolumab 300 mg; Participants will receive 300 milligram (mg) anifrolumab as an intravenous infusion every 4 weeks for 48 weeks.; Other Names: MEDI-546
Experimental: Anifrolumab (MEDI-546) 1000 mg; Participants will receive 1000 mg anifrolumab as an intravenous infusion every 4 weeks for 48 weeks.	Biological: Anifrolumab 1000 mg; Participants will receive 1000 mg anifrolumab as an intravenous infusion every 4 weeks for 48 weeks.; Other Names: MEDI-546
Placebo Comparator: Matching Placebo; Participants will receive placebo matched to anifrolumab intravenous (IV) infusion every 4 weeks for 48 weeks.	Other: Placebo; Participants will receive placebo matched to anifrolumab intravenous (IV) infusion every 4 weeks for 48 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving an Systemic Lupus Erythematosus (SLE) Responder Index [SRI (4)] Response With Oral Corticosteroids (OCS) Tapering at Day 169	An SRI (4) responder defined as a participant who had 1) a reduction in baseline Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of greater than or equal to (>=) 4 points; 2) no worsening of disease from baseline as measured by the Physician Global Assessment (MDGA) (worsening was defined as an increase of >= 0.3 from baseline on a 0 to 3.0 visual analog scale); and 3) no new British Isles Lupus Assessment Group 2004 (BILAG-2004) Index 'A' organ system score and no more than one new or worsening BILAG-2004 Index 'B' organ system score. OCS tapering requires a sustained reduction of OCS from Day 85 through Day 169 [less than 10 milligram per day (mg/day) and less or equal to the dose received on Day 1]. SRI was analyzed by a logistic regression model.	Day 169
Percentage of Type I Interferon (IFN) Test High Participants Achieving an Systemic Lupus Erythematosus Responder Index (SRI) (4) Response With Oral Corticosteroids (OCS) Tapering at Day 169	Type I IFN signature in whole blood assessed by using a 4-gene diagnostic test. The blood samples collected were to be used to prospectively identify participants as IFN test-high or test-low. The results of this test were used to stratify participants. An SRI (4) Responder was defined as a participant who had 1) a reduction in baseline SLEDAI-2K disease activity score of >= 4 points; 2) no worsening of disease from baseline as measured by the Physician Global Assessment (MDGA) (worsening was defined as an increase of >= 0.3 from baseline on a 0 to 3.0 visual analog scale); and 3) no new British Isles Lupus Assessment Group 2004 (BILAG-2004) Index A organ system score and no more than one new or worsening BILAG-2004 Index B organ system score. OCS tapering requires a sustained reduction of OCS from Day 85 through Day 169 [less than 10 mg/day and less or equal to the dose received on Day 1]. SRI was analyzed by a logistic regression model.	Day 169

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving an Systemic Lupus Erythematosus (SLE) Responder Index [SRI (4)] Response With Oral Corticosteroids (OCS) Tapering at Day 365	An SRI (4) Responder was defined as a participant who had 1) a reduction in baseline SLEDAI-2K disease activity score of >= 4 points; 2) no worsening of disease from baseline as measured by the MDGA (worsening was defined as an increase of >= 0.3 from baseline on a 0 to 3.0 visual analog scale); and 3) no new British Isles Lupus Assessment Group 2004 (BILAG-2004) Index A organ system score and no more than one new or worsening BILAG-2004 Index B organ system score. OCS tapering requires a sustained reduction of OCS from Day 281 through Day 365 (less than 10 mg/day and less or equal to the dose received on Day 1). SRI was analyzed by a logistic regression model.	Day 365
Percentage of Participants on Oral Corticosteroids (OCS) >=10 mg/Day of Prednisone or Equivalent at Baseline Who Were Able to Taper to Less Than or Equal to (<=) 7.5 mg/Day at Day 365	Participants on OCS >=10 mg/day of prednisone or equivalent at baseline who were able to taper to <= 7.5 mg/day at Day 365 were evaluated.	Day 365
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Adverse Events of Special Interest (AESIs) and Treatment-Emergent Serious Adverse Events (TESAEs)	An adverse event (AE) was any untoward medical occurrence in a study participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A serious AE (SAE) was an AE resulting in any of following outcomes or deemed significant for any other reason: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly (in offspring of participant). AEs may be treatment emergent (TE) [that is, occurring after initial receipt of investigational product] or non-TE. An AESI is one of scientific and medical concern specific to understanding biologics and requires close monitoring and rapid communication by investigator to sponsor.	Day 1 (Baseline) to Day 422 (End of Study)
Number of Participants With Clinically Significant Laboratory Abnormalities in Investigations Reported as Treatment-Emergent Adverse Events	Any medically significant change in laboratory evaluations were recorded as Treatment emergent adverse events.	Day 1 (Baseline) to Day 422 (End of Study)
Number of Participants With Vital Signs Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs)	Vital sign parameters are temperature, blood pressure, respiratory rate, heart rate and weight. Vital signs abnormalities were reported as TEAEs.	Day 1 (Baseline) to Day 422 (End of Study)
Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs)	Any medically significant changes from the screening ECG was recorded as TEAEs. An abnormal ECG findings such as QT prolonged were reported as treatment emergent adverse events.	Day 1 (Baseline) to Day 422 (End of Study)
Percentage of SLE Participants With Positive Anti-drug Antibody (ADA)	Anti-drug antibody responses to anifrolumab in serum were evaluated.	Days 1, 85, 141, 169, 253, 337 (Treatment Phase), 365, 396, and 422 (Follow-up Period)
Neutralization Ratio of 21-Gene Type I Interferon (IFN) Signature for Participants With Positive Baseline Pharmacodynamic (PD) Gene Signature	The PD positive and negative gene signature was determined by comparing the expression of type I IFN-inducible genes in a 21-gene panel in study participants relative to pooled normal blood collected from healthy participants.	Days 29, 85, 141, 169, 253, 337 (treatment phase), on Days 365, 396, and 422 (follow up period)
Maximum Observed Plasma Concentration (Cmax) of Anifrolumab at Day 1, 169 and 337	Maximum plasma concentration (Cmax) was defined as the peak plasma level of anifrolumab, derived from plasma concentration -time data.	Pre-infusion and 15 minutes post-infusion on Day 1, 169 and 337
Accumulation Ratio of Maximum Observed Plasma Concentration (Cmax,AR) of Anifrolumab	Accumulation ratio for maximum plasma concentration (Cmax,AR) of anifrolumab after multiple administration at Day 169 and 337 was calculated.	Pre-infusion and 15 minutes post-infusion on Day 169 and 337
Trough Concentration (Ctrough) of Anifrolumab at Day 29, 169 and 365	Trough concentration (Ctrough) of anifrolumab at Day 29, 169 and 365 were calculated.	Pre-infusion and 15 minutes post-infusion on Day 29, 169 and 365
Accumulation Ratio of Trough Concentration (Ctrough,AR) of Anifrolumab at Day 169 and 365	Accumulation ratio for trough concentration (Ctrough,AR) of anifrolumab after multiple administration at Day 169 and 365 was calculated.	Pre-infusion and 15 minutes post-infusion on Day 169 and 365

Collaborators and Investigators

• Sponsor: MedImmune LLC
• Investigators: Study Director: Warren Greth, MD, MedImmune LLC

Publications and helpful links

General Publications

• 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.
• Brohawn PZ, Streicher K, Higgs BW, Morehouse C, Liu H, Illei G, Ranade K. Type I interferon gene signature test-low and -high patients with systemic lupus erythematosus have distinct gene expression signatures. Lupus. 2019 Nov;28(13):1524-1533. doi: 10.1177/0961203319885447. Epub 2019 Oct 29.
• Casey KA, Smith MA, Sinibaldi D, Seto NL, Playford MP, Wang X, Carlucci PM, Wang L, Illei G, Yu B, Wang S, Remaley AT, Mehta NN, Kaplan MJ, White WI. Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2021 Mar;73(3):459-471. doi: 10.1002/art.41518. Epub 2021 Feb 15.
• Casey KA, Guo X, Smith MA, Wang S, Sinibaldi D, Sanjuan MA, Wang L, Illei GG, White WI. Type I interferon receptor blockade with anifrolumab corrects innate and adaptive immune perturbations of SLE. Lupus Sci Med. 2018 Nov 22;5(1):e000286. doi: 10.1136/lupus-2018-000286. eCollection 2018. Erratum In: Lupus Sci Med. 2018 Dec 22;5(1):e000286corr1.
• Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, Illei GG, Drappa J, Wang L, Yoo S; CD1013 Study Investigators. Anifrolumab, an Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376-386. doi: 10.1002/art.39962.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: September 9, 2011
• First Submitted That Met QC Criteria: September 21, 2011
• First Posted (Estimate): September 22, 2011

Study Record Updates

• Last Update Posted (Estimate): October 7, 2016
• Last Update Submitted That Met QC Criteria: August 29, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Systemic Lupus Erythematosus; Anifrolumab; MEDI-546
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: CD-IA-MEDI-546-1013