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

• ClinicalTrials.gov Identifier: NCT01438489
• Recruitment Status: Completed
• First Posted: September 22, 2011
• Results First Posted: August 15, 2016
• Last Update Posted: October 7, 2016
• Sponsor: MedImmune LLC
• Information provided by (Responsible Party): MedImmune LLC

Tracking Information

• First Submitted Date: September 9, 2011
• First Posted Date: September 22, 2011
• Results First Submitted Date: July 5, 2016
• Results First Posted Date: August 15, 2016
• Last Update Posted Date: October 7, 2016
• Study Start Date: January 2012
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 5, 2016)

• Percentage of Participants Achieving an Systemic Lupus Erythematosus (SLE) Responder Index [SRI (4)] Response With Oral Corticosteroids (OCS) Tapering at Day 169 [ Time Frame: 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.
• 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 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: September 21, 2011)

Achievement of response in a systemic lupus erythematosus (SLE) responder index [ Time Frame: Day 169 (or 6 months) ]

Number and percentage of participants achieving a response in an SLE responder index at Day 169 (or 6 months)

Current Secondary Outcome Measures (submitted: August 29, 2016)

• Percentage of Participants Achieving an Systemic Lupus Erythematosus (SLE) Responder Index [SRI (4)] Response With Oral Corticosteroids (OCS) Tapering at Day 365 [ Time Frame: 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.
• 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 [ Time Frame: 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.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Adverse Events of Special Interest (AESIs) and Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: Day 1 (Baseline) to Day 422 (End of Study) ]
  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.
• Number of Participants With Clinically Significant Laboratory Abnormalities in Investigations Reported as Treatment-Emergent Adverse Events [ Time Frame: Day 1 (Baseline) to Day 422 (End of Study) ]
  Any medically significant change in laboratory evaluations were recorded as Treatment emergent adverse events.
• Number of Participants With Vital Signs Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 (Baseline) to Day 422 (End of Study) ]
  Vital sign parameters are temperature, blood pressure, respiratory rate, heart rate and weight. Vital signs abnormalities were reported as TEAEs.
• Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 (Baseline) to Day 422 (End of Study) ]
  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.
• Percentage of SLE Participants With Positive Anti-drug Antibody (ADA) [ Time Frame: Days 1, 85, 141, 169, 253, 337 (Treatment Phase), 365, 396, and 422 (Follow-up Period) ]
  Anti-drug antibody responses to anifrolumab in serum were evaluated.
• Neutralization Ratio of 21-Gene Type I Interferon (IFN) Signature for Participants With Positive Baseline Pharmacodynamic (PD) Gene Signature [ Time Frame: Days 29, 85, 141, 169, 253, 337 (treatment phase), on Days 365, 396, and 422 (follow up period) ]
  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.
• Maximum Observed Plasma Concentration (Cmax) of Anifrolumab at Day 1, 169 and 337 [ Time Frame: Pre-infusion and 15 minutes post-infusion on Day 1, 169 and 337 ]
  Maximum plasma concentration (Cmax) was defined as the peak plasma level of anifrolumab, derived from plasma concentration -time data.
• Accumulation Ratio of Maximum Observed Plasma Concentration (Cmax,AR) of Anifrolumab [ Time Frame: Pre-infusion and 15 minutes post-infusion on Day 169 and 337 ]
  Accumulation ratio for maximum plasma concentration (Cmax,AR) of anifrolumab after multiple administration at Day 169 and 337 was calculated.
• Trough Concentration (Ctrough) of Anifrolumab at Day 29, 169 and 365 [ Time Frame: Pre-infusion and 15 minutes post-infusion on Day 29, 169 and 365 ]
  Trough concentration (Ctrough) of anifrolumab at Day 29, 169 and 365 were calculated.
• Accumulation Ratio of Trough Concentration (Ctrough,AR) of Anifrolumab at Day 169 and 365 [ Time Frame: Pre-infusion and 15 minutes post-infusion on Day 169 and 365 ]
  Accumulation ratio for trough concentration (Ctrough,AR) of anifrolumab after multiple administration at Day 169 and 365 was calculated.

Original Secondary Outcome Measures (submitted: September 21, 2011)

Achievement of response in a systemic lupus erythematosus (SLE) responder index [ Time Frame: Day 365 (or 1 year) ]

Number and percentage of participants achieving a response in an SLE responder index at Day 365 (or 1 year)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of the Efficacy and Safety of MEDI-546 in Systemic Lupus Erythematosus
• Official Title: A Phase 2, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects With Systemic Lupus Erythematosus
• Brief Summary: 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.
• 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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Systemic Lupus Erythematosus

Intervention

• Biological: Anifrolumab 300 mg
  Participants will receive 300 milligram (mg) anifrolumab as an intravenous infusion every 4 weeks for 48 weeks.
  Other Name: MEDI-546
• Biological: Anifrolumab 1000 mg
  Participants will receive 1000 mg anifrolumab as an intravenous infusion every 4 weeks for 48 weeks.
  Other Name: MEDI-546
• Other: Placebo
  Participants will receive placebo matched to anifrolumab intravenous (IV) infusion every 4 weeks for 48 weeks.

Study Arms

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

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.
• 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.
• 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, 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 19, 2014): 626
• Original Estimated Enrollment (submitted: September 21, 2011): 300
• Actual Study Completion Date: April 2015
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil, Bulgaria, Colombia, Czech Republic, Hungary, India, Korea, Republic of, Mexico, Peru, Poland, Romania, Taiwan, Ukraine, United States
• Removed Location Countries: Hong Kong

Administrative Information

• NCT Number: NCT01438489
• Other Study ID Numbers: CD-IA-MEDI-546-1013
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: MedImmune LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: MedImmune LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Warren Greth, MD; MedImmune LLC

• PRS Account: MedImmune LLC
• Verification Date: August 2016