Proof of Concept Study of SAR443122 in Patients With Cutaneous Lupus Erythematosus

Study Overview
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Brief Summary
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Primary Objective: Assess the efficacy of SAR443122 in cutaneous lupus erythematosus (CLE) Secondary Objectives: Assess the effect of SAR443122 on the physician's global assessment of disease activity (PhysGA - disease activity) Assess the effect of SAR443122 on CLE induced itch and overall pain Assess the effect of SAR443122 on the proportion of disease activity responders compared to placebo Assess the effect of SAR443122 on the CLASI components score Assess the effect of SAR443122 on the Investigator's global assessment for CLE (IGA-CLE) Assess oral cavities for patients with oral lesions Assess the disease specific quality of life (QoL) Assess the safety and tolerability of SAR443122 in patients with CLE Assess the pharmacokinetics (PK) exposure of SAR443122 in patients with CLE

Detailed Description
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Total study duration per participant will be up 20 weeks including: A screening period of up to 4 weeks A treatment period of 12 weeks A post treatment follow-up period of 4 weeks

Official Title
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Randomized, Double-blind, Placebo Controlled, Proof of Concept Study Assessing the Efficacy and Safety of the RIPK1-inhibitor SAR443122 in Patients With Moderate to Severe Subacute or Discoid/Chronic Cutaneous Lupus Erythematosus

Conditions
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Cutaneous Lupus Erythematosus

Intervention / Treatment
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* Drug: SAR443122
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants with cutaneous lupus erythematosus either in the form of discoid/chronic cutaneous lupus erythematosus or subacute cutaneous lupus erythematosus for at least 3 months before Screening. Participants with histologically confirmed and documented diagnosis within one year prior to Screening or during Screening period prior to randomization. Active cutaneous lupus erythematosus skin lesions and a Cutaneous Erythematosus. Disease Area and Severity Index activity (CLASI-A) ≥10 both at Screening and Baseline. Participant who is candidate for systemic treatment per Investigator's judgement. Exclusion criteria: Systemic lupus erythematosus according to the 2012 SLICC criteria with major organ involvement. Suspected or proven drug induced lupus erythematosus, including patients with positive antihistone autoantibody tests. Autoimmune disease(s) other than systemic lupus erythematosus. Active skin diseases that may interfere with the study or study assessments. Exclusion related to tuberculosis, non-tuberculous mycobacterial infections, HIV, HBV, HCV, Herpes zoster, COVID-19 and other recurrent or recent serious infections. Prolonged QTcF ≥ 450 ms (by Fridericia formula) or clinically significant findings on electrocardiogram (ECG). Cannot avoid excessive UV exposure 4 weeks prior to baseline and during the study. Routine sun exposure through work are permitted but requires the use of sun block to sun exposed areas for at least 4 weeks prior to baseline and during the study. Concomitant treatment with topical immunosuppressants beyond a stable regimen of low to medium potency topical corticosteroids and/or topical calcineurin inhibitors during the study and two weeks before baseline visit. Initiation and/or changes in dosage of chloroquine/hydroxychloroquine within 12 weeks prior to Screening visit (or during Screening period) and/or the dose exceeding 2.3 mg/kg/day for chloroquine or 400 mg/day for hydroxychloroquine. Systemic treatments for cutaneous or systemic lupus erythematosus or immunosuppressive therapy for autoimmune disease other than the study medication. Systemic corticosteroids treatment <4 weeks before baseline visit. Live vaccine(s) within 1 month prior to Screening, or plans to receive such vaccines during the study. Laboratory abnormalities at the Screening visit. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: SAR443122<br>SAR443122 for 12 weeks | Drug: SAR443122<br>* Pharmaceutical form: Capsule Route of administration: Oral<br>|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Placebo<br>* Pharmaceutical form: Capsule Route of administration: Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in Cutaneous Erythematosus Disease Area and Severity Index activity (CLASI-A) sub-score | The Cutaneous Erythematosus Disease Area and Severity Index (CLASI) is a clinician rated scale composed of 56 items designed to assess the disease activity and damage in CLE in adults. The disease activity (CLASI-A) sub-score ranges from 0 to 70: 0-9 indicating mild disease, 10-20 indicating moderate disease, and 21-70 indicating severe disease. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with physician's global assessment of disease activity (PhysGA - disease activity) of 0 or 1 (disease free or almost disease free) | The PhysGA-disease activity is a 5 point-Lickert scale instrument designed to assess physician-reported disease activity ranging from Not active at all to Extremely active. | Week 12 | 
| Change from baseline in patients reported daily worst itch using Peak Pruritus Numerical Rating Scale (itch-NRS) | The itch-NRS is a single item patient-reported outcome (PRO) tool that patients will use to report the intensity of their pruritus (itch) during a daily recall period. Patients will be asked to rate their worst itch on a 0 (No itch) to 10 (Worst itch imaginable) NRS. | Baseline to Week 12 | 
| Change from baseline in patients reported daily worst pain using Peak Pain Numerical Rating Scale (Pain-NRS) | The Pain-NRS is a single item PRO tool that patients will use to report the intensity of their CLE-related pain (skin, oral, genital) during a daily recall period. Patients will be asked to rate their worst pain on a 0 (No pain) to 10 (Worst pain imaginable) NRS. | Baseline to Week 12 | 
| Proportion of CLASI-A50 and CLASI-A75 responders | The CLASI-A50/75 response is defined as a patient achieved a decrease by at least 50%/75% of CLASI-A sub-score from baseline. | Week 12 | 
| Change from baseline in CLASI components' score | Change from baseline in CLASI components' score over time | Baseline up to Week 12 | 
| Proportion of patients with the Investigator's global assessment for CLE (IGA-CLE) score of 0 or 1 (clear or almost clear) | The IGA-CLE is a clinician reported outcome that allows for clinicians to assess the overall disease activity of CLE using a 5-point scale from 0 (clear) to 4 (severe). | Week 12 | 
| Change from baseline in the Oral Health Impact Profile (OHIP-14) for patients with oral lesions at baseline | OHIP-14 is a PRO questionnaire measures people's perception of dysfunction, discomfort and disability attributed to oral conditions in adults. It is composed of 14 items that assess seven different dimensions. The OHIP-14 scores can range from 0 to 56 and higher OHIP-14 scores indicate worse oral-health-related quality of life. | Baseline to Week 12 | 
| Change from baseline in SKINDEX-29+3 total score | Skindex-29 is a PRO measure designed to assess the effects of skin disease on patients' health-related quality of life in adults. It contains 29 items, distributed across 3 domains. Individual items are scored from 0 to100 in 25-point increments with 100 representing maximal disability. The Skindex 29+3 includes a fourth subscale (3 questions) to assess lupus-specific issues. | Baseline to Week 12 | 
| Total number of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) |  | Screening up to end of study (Week 16) | 
| Percent of TEAEs, SAEs and AESIs |  | Screening up to end of study (Week 16) | 
| Percent of potentially clinically significant abnormalities (PCSAs) | Percent of potentially clinically significant abnormalities (PCSAs) in laboratory tests, electrocardiogram (ECG) or vital signs through end of study | Screening up to end of study (Week 16) | 
| SAR443122 plasma concentration |  | Day 1, Day 57 and Day 85 | 
| Assessment of pharmacokinetic (PK) parameter: Cmax | Maximum plasma concentration | Day 1, Day 57 and Day 85 | 
| Assessment of PK parameter: tmax | Time to reach Cmax | Day 1, Day 57 and Day 85 | 
| Assessment of PK parameter: AUC0-tau | Area under the plasma concentration - time curve over the dosing interval | Day 1, Day 57 and Day 85 | 
| Assessment of PK parameter: t1/2z | Elimination half-life | Day 1, Day 57 and Day 85 |