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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Biological: Anifrolumab 300 mg
* Biological: Anifrolumab 1000 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEDI-546, Anifrolumab, Systemic Lupus Erythematosus