A Study to Investigate the Efficacy and Safety of Anifrolumab in Adults With Chronic and/or Subacute Cutaneous Lupus Erythematosus

Study Overview
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Brief Summary
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This study aims to evaluate the efficacy and safety of a subcutaneous (SC) treatment regimen of dose A of anifrolumab versus placebo in adult participants with cutaneous lupus erythematosus (CLE).

Detailed Description
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The study will have a randomized, double-blind, placebo-controlled design, followed by an open-label treatment period. The study will include: Screening Period (within 6-weeks [42 days] prior to randomization). Double-blinded Treatment Period (24 weeks) Open-label Treatment Period (28 weeks) Safety Follow-up Period (12 weeks) Eligible participants will be randomized in a 1:1 ratio to receive either dose A of anifrolumab or placebo through SC route. The study duration for a participant will be a maximum of 71 weeks.

Official Title
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A Multicenter, Randomized, Double Blind, Placebo Controlled, Phase III Study to Evaluate the Efficacy and Safety of Anifrolumab in Adults With Chronic and/or Subacute Cutaneous Lupus Erythematosus Who Are Refractory and/or Intolerant to Antimalarial Therapy

Conditions
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Cutaneous Lupus Erythematosus

Intervention / Treatment
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* Combination Product: Anifrolumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Participants must have a confirmed diagnosis of CLE. Diagnosis must be clinically and histologically confirmed with the following: CLASI-A total score ≥ 10 points at Screening and confirmed at randomization. Combined CLASI-A score for Erythema and Scale/Hypertrophy components ≥ 7 points. They should have experienced inadequate response or be intolerant to anti-malarial therapy. In case an anti-malarial treatment was never given, they should have tried one of the following medications for CLE: topical calcineurin inhibitors, systemic glucocorticoids, or a conventional immunosuppressant. Participants should have no medical history or signs or symptoms of active or prior tuberculosis infection (TB) and the same should reflect in chest radiograph or a chest CT scan result. No history of latent TB prior to initial Screening Visit. The participant must undergo an IFN-γ release assay IGRA (e.g., QFT-G test) test for TB. Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Females who have been or are sexually active with an intact cervix must have documentation of a cervical cancer screening as per local guidelines (Pap smear or HPV tests). Participants should have a COVID-19 negative PCR or antigen test result as per local policies at Screening. They should also not have had known or suspected COVID-19 exposure within 2 weeks prior to screening based on the COVID-19 questionnaire. If there is a known or suspected exposure, a participant must be negative upon retest obtained after 2 weeks and must remain asymptomatic for inclusion in the study. Exclusion criteria: Participants are excluded from the study if any of the following criteria apply: History or evidence of suicidal ideation. Severe or life-threatening SLE. Active SLE or Sjögren's Syndrome. Any active skin conditions other than CLE that may interfere with the study. History of recurrent infection requiring hospitalization and IV antibiotics. Known history of primary immunodeficiency, splenectomy, or any underlying condition that makes the participant prone to infection, or a positive result for HIV infection at Screening. Confirmed positive test for hepatitis B serology at screening. Presence of active hepatitis C infection. Any severe case, as defined by study guidelines, of herpes zoster infection. Any clinical cytomegalovirus (CMV) or Epstein-Barr virus infection that has not completely resolved. Any severe case, as defined by study guidelines, of herpes zoster infection at any time prior to randomization (Day 1). Any herpes zoster infection that has not completely resolved within 12 weeks prior to signing the informed consent form (ICF). Any clinical CMV or Epstein Barr virus infection that has not completely resolved within 12 weeks prior to signing the ICF. Clinically significant chronic infection within 8 weeks prior to signing the ICF or any infection requiring hospitalization or treatment with IV anti-infectives not completed at least 4 weeks prior to signing the ICF. COVID-19 infection History of severe COVID-19 infection or any prior COVID-19 infection with documented long COVID-19 and/or clinically significant unresolved complications due to COVID-19 infection. Mild/asymptomatic COVID-19 infection within the last 6 weeks prior to first dosing. Confirmed or probable COVID-19 infection based on clinical symptoms and radiologic imaging within 3 months prior to Day 1. COVID-19 vaccine received within 30 days of randomization (Day 1). Participants who do not meet the study restrictions for using all biologics including anifrolumab, B- cell depleting therapies (eg, rituximab), and investigational product for CLE. A known history of allergy or reaction to any component of the study intervention formulation or history of anaphylaxis to any human gamma globulin therapy. Any history of an anaphylactic reaction to human proteins, or monoclonal antibodies. At screening, if participants do not meet the eligibility criteria assessed based on laboratory test results e.g tests for total bilirubin, serum creatinine etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Interventional Model Description: This is a parallel group treatment study with two arms.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anifrolumab<br>The participants will receive dose A of anifrolumab as a SC injection from Week 0/Day 1 upto and including week 51. | Combination Product: Anifrolumab<br>* Anifrolumab will be provided as a solution for injection in accessorized pre-filled syringe (aPFS).<br>|
| Placebo Comparator: Placebo<br>The participant will receive placebo as a SC injection from Week 0/Day 1 to Week 23. From Week 24 the participants will receive dose A of anifrolumab up to and including Week 51. | Other: Placebo<br>* Matching placebo solution for injection in aPFS.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Cutaneous Lupus Erythematosus Disease Area and Severity Index - Activity (CLASI-A) CLASI-A Responder Index-7 (CRI- 7) response (United States) | CLASI is index for assessing cutaneous lesions of systemic lupus erythematosus (SLE). It consists of 2 scores: i) activity of disease, and ii) measure of damage. Activity score considers factors as erythema, scale/hypertrophy, mucous membrane lesions, recent hair loss and non-scarring alopecia. Damage score represents dyspigmentation, scarring/atrophy/panniculitis, and scarring of scalp. A 7-point reduction CLASI-A is established as clinically meaningful improvement in disease for CLE and as being impactful for patients. CLASI-A score is indicative of severity of skin manifestations of CLE, and achieving a CLASI-A total score of 9 or below is an accepted threshold for mild disease. At Week 24, CLASI-A Responder Index-7 (CRI-7) response will be assessed, and a responder (yes/no) is a participant who meets all following criteria: • ≥ 7-point reduction from baseline in CLASI-A score. • Total CLASI-A score at Week 24 of ≤ 9. A participant who does not meet these criteria is non-responder. | At Week 24 | 
| Number of participants with CLASI-70 response (European Union and Rest of the World) | The CLASI is a validated index used for assessing the cutaneous lesions of SLE. The CLASI instrument will be used at each study visit to capture individual skin manifestation scores. CLASI-70 responder (Yes/No) is defined as a participant who achieves a 70% reduction relative to baseline in CLASI-A score. Otherwise, the participant is considered a non-responder. | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in total erythema score (United States, European Union and Rest of the World) | The CLASI is a validated index used for assessing the cutaneous lesions of SLE. The CLASI instrument will be used at each study visit to capture individual skin manifestation scores. Assessment of CLASI-A erythema score captures changes in erythema, a clinically important feature in CLE patients. A CLASI-A erythema score of 0 is absent, 1 is pink faint erythema, 2 is red, 3 is dark red; purple/violaceous/crusted/hemorrhagic. Assessment of CLASI-A erythema score captures changes in erythema, a clinically important feature in CLE patients. | At Week 24 | 
| Percent change from baseline in total scale/hypertrophy score (United States, European Union and Rest of the World) | Assessment of CLASI-A scale/hypertrophy score captures extent of hypertrophy, a clinically important feature in CLE patients. The CLASI is a validated index used for assessing the cutaneous lesions of SLE. CLASI-A Scale/Hypertrophy can be measured as 0, 1, and 2 where 0 is absent, 1 is scale, and 2 is verrucuos and hypertrohic. | At Week 24 | 
| Number of participants with CLASI-A Responder Index-7 (CRI-7) response (United States) | The CLASI is a validated index used for assessing the cutaneous lesions of SLE. The CLASI instrument will be used at each study visit to capture individual skin manifestation scores. A 7-point reduction CLASI-A is established as clinically meaningful improvement in disease for CLE and as being impactful for patients. Achieving a CLASI-A total score of 9 or below is an accepted threshold for mild disease. At Week 12, CLASI-A Responder Index-7 (CRI-7) response will be assessed, and a responder (yes/no) is defined as a participant who meets all the following criteria: ≥ 7-point reduction from baseline in CLASI-A score. Total CLASI-A score of ≤ 9. A participant who does not meet these criteria is a non-responder. | At Week 12 | 
| Number of participants with CLASI-70 response (European Union and Rest of the World) | The CLASI is a validated index used for assessing the cutaneous lesions of SLE. CLASI-70 responder is defined as a participant who achieves a 70% reduction relative to baseline in CLASI-A score. Otherwise, the participant is considered a non-responder. | At Week 12 | 
| Number of participants with Cutaneous Lupus Activity of Physician's Global Assessment-Revised (CLA-IGA-R) erythema score of 0 or 1 (United States) | The CLA-IGA-R is an assessment tool that scores the three key disease components (erythema; OMC [other morphological characteristics] and follicular activity) of CLE independently. The CLA-IGA-R erythema is scored on a five-point binary scale that provides a global clinical assessment ranging from 0 to 4, where 0 indicates clear, 1 is almost clear, 2 is mild, 3 is moderate, and 4 indicates severe CLE. On all IGA scales, a decrease in score relates to an improvement in signs and symptoms. Assessment of CLA-IGA-R erythema score captures changes in erythema, a clinically important feature in CLE patients. A decrease in score relates to an improvement in signs and symptoms. | At Week 24 | 
| Number of participants with Cutaneous Lupus Activity of Physician's Global Assessment-Revised (CLA-IGA-R) other morphological characteristics (OMC) score of 0 (United States) | The CLA-IGA-R is an assessment tool that scores the three key disease components (erythema; OMC and follicular activity) of CLE independently. The CLA-IGA-R OMC is scored on a five-point binary scale that provides a global clinical assessment ranging from 0 to 4, where 0 indicates clear, 1 is almost clear, 2 is mild, 3 is moderate, and 4 indicates severe CLE. Assessment of CLA-IGA-R OMC score captures other morphological changes in CLE patients. A decrease in score relates to an improvement in signs and symptoms. | At Week 24 | 
| Number of participants with ≥ 7-point reduction from baseline in CLASI-A total score (United States) | The CLASI is a validated index used for assessing the cutaneous lesions of SLE. It consists of 2 separate scores: i) activity of the disease, and ii) measure of damage. The CLASI instrument will be used at each study visit to capture individual skin manifestation scores. A 7-point reduction CLASI-A is established as clinically meaningful improvement in disease for CLE and as being impactful for patients. Achieving a CLASI-A total score of 9 or below is an accepted threshold for mild disease. | At Week 24 | 
| Number of participants with a total CLASI-A total score of ≤ 9 (United States) | The CLASI is a validated index used for assessing the cutaneous lesions of SLE. The CLASI instrument will be used at each study visit to capture individual skin manifestation scores. It consists of 2 separate scores: i) activity of the disease, and ii) measure of damage. A 7-point reduction CLASI-A is established as clinically meaningful improvement in disease for CLE and as being impactful for participants. Achieving a CLASI-A total score of 9 or below is an accepted threshold for mild disease. | At Week 24 | 
| Number of participants with CLA-IGA-R OMC score of 0 or 1 (United States) | The CLA-IGA-R is an assessment tool that scores the three key disease components (erythema; OMC and follicular activity) of CLE independently. The CLA-IGA-R OMC is scored on a five-point binary scale that provides a global clinical assessment ranging from 0 to 4, where 0 indicates clear, 1 is almost clear, 2 is mild, 3 is moderate, and 4 indicates severe CLE. Assessment of CLA-IGA OMC score captures other morphological changes in CLE patients. A decrease in score relates to an improvement in signs and symptoms. | At Week 24 | 
| Number of participants with CLA-IGA-R follicular activity score of 0 (United States) | The CLA-IGA-R is an assessment tool that scores the three key disease components (erythema; OMC and follicular activity) of CLE independently. CLA-IGA-R follicular activity provides a global clinical assessment on a 2-point binary scale ranging from 0 to 1, where 0 indicates absent and 1 indicates present. A decrease in score relates to an improvement in signs and symptoms. | At Week 24 | 
| Change from baseline in Skindex-29+3 domain scores (United States, European Union and Rest of the World) | The Skindex-29+3 is based on a previous instrument, the Skindex-29 and has been modified to include items related to CLE. The instrument consists of 33 items, which are used to calculate 4 domains: Symptoms (7 items), emotions (10 items), Functioning (12 items), and Lupus-specific (3 items). The remaining item asks the participants to rate how often they worry about side effects from treatment; however, this item is not used to calculate the domain scores. The response options are on a 5-point verbal rating scale, ranging from 1 (Never) to 5 (All the time). The instrument has a recall period of the previous 4 weeks. Each domain score ranges from 0 to 100 points, with higher scores indicating worse health-related quality of life. The symptom domain in the Skindex-29+3 evaluates the symptom burden of the disease and includes symptom concepts such as pain, itching, burning, stinging, and sensitivity. | At Week 24 | 
| Number of participants with CLASI-70 responders upto Week 52 (European Union and Rest of the World) | The CLASI is a validated index used for assessing the cutaneous lesions of SLE. CLASI-70 responder is defined as a participant who achieves a 70% reduction relative to baseline in CLASI-A score. Otherwise, the participant is considered a non-responder. Amongst participants randomized to anifrolumab during the double-blind treatment period, the number of participants who maintained a CLASI-70 response from Week 24 upto Week 52 will be evaluated. | Upto Week 52 | 
| Serum trough (pre-dose) concentrations of anifrolumab | The Ctrough of subcutaneously administered anifrolumab in participants with chronic and/or subacute CLE will be evaluated. | Double-blind: Pre-dose on Day 1 (Week 0), Weeks 1, 4, 12, 24; Open-label: Weeks 40, and 52 or early discontinuation visit [EVD] and follow-up visit (13 Weeks after last dose) | 
| Number of participants with positive antidrug antibody | The immunogenicity of subcutaneously administered anifrolumab in participants with chronic and/or subacute CLE will be evaluated. | Double-blind: Pre-dose on Day 1 (Week 0), Weeks 12, and 24; Open-label: Pre-dose on Weeks 40, and 52 or EVD and follow-up visit (13 weeks after last dose) | 
| Percent change from baseline in suppression of the interferon 21 gene | The pharmacodynamic of subcutaneously administered anifrolumab in participants with chronic and/or subacute CLE will be evaluated. | Double-blind: Day 1 (Week 0), Week 4, Weeks 12, and 24; Open-label: Week 40, and 52 or EVD and follow-up visit (13 weeks after last dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lupus erythematosus, Cutaneous lupus erythematosus, anifrolumab, Cutaneous Lupus Erythematosus Disease Area Severity Index, Cutaneous Lupus Erythematosus Disease Area Severity Index responder index 7