A Study to Evaluate SAR441566 Efficacy and Safety in Adults With Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
This is a parallel group, Phase 2, randomized, double-blind, placebo controlled, 5-arm, international, multicenter, 12-week proof of concept, dose finding study. It is designed to assess efficacy and safety of treatment with SAR441566 for 12 weeks. It will be conducted in male and female adult participants with moderate-to-severe rheumatoid arthritis (RA) not adequately controlled on methotrexate (MTX) and biologic/targeted synthetic disease modifying anti-rheumatic drug (DMARD) naive. Study treatment includes investigational medicinal product (IMP: SAR441566 or placebo) added-on to a background therapy of MTX. Study details include a run-in period (6 weeks ± 3 days) before randomization to determine eligibility, a treatment period (12 weeks ± 3 days) and a post-treatment period (safety follow-up) (2 weeks ± 3 days). The total number of scheduled study visits will be 8.

Detailed Description
-----------------
The overall study duration for each participant will be approximately up to 149 days.

Official Title
-----------------
A Phase 2 Randomized, Double-blind, Placebo-controlled, Dose-ranging, Efficacy and Safety Study of SAR441566 Plus Methotrexate in Adults With ModeratetoSevere Rheumatoid Arthritis

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: SAR441566
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of adult-onset RA classified by ACR/EULAR 2010 revised classification criteria for RA of at least 3 months duration, with the onset of signs and symptoms of RA of at least 6 months duration Moderate-to-severely active RA, defined as: persistently active disease >= 6 tender and >= 6 swollen joints high sensitivity C-reactive protein > 5 mg/L Continuous treatment with MTX for at least 12 consecutive weeks prior to randomization and with stable dose/means of administration at least 6 weeks prior to the screening visit MTX - 10 to 25 mg/week (or per local labeling requirements for the treatment of RA if the dose range differs, eg, for Japan, a stable dose of MTX is 6 to 16 mg/week) and folic/folinic acid (as part of MTX regimen) Inadequate clinical response to MTX at a dose of 10-25 mg/week after proper dose escalation according to local standards (eg, for Japan, a stable dose of MTX is 6 to 16 mg/week) BMI within the range [18 - 35] kg/m^2 (inclusive) Exclusion Criteria: Immunologic disorder other than RA, with the exception of secondary Sjogren's syndrome associated with RA, and medically controlled diabetes or thyroid disorder as per Investigator's judgement Any condition requiring oral, intravenous, IM, or intra-articular glucocorticoid therapy Uncontrolled polymyalgia rheumatica or fibromyalgia History of recurrent or recent serious infection (eg, pneumonia, septicemia) or infection(s) requiring hospitalization or treatment with IV anti-infectives (antibiotics, antivirals, antifungals, antihelminthics) within 30 days prior to D1. Infections(s) requiring oral anti-infectives (antibiotics, antivirals, antifungals, antihelminthics) within 14 days prior to D1 Known history of or suspected significant current immunosuppression, including history of invasive opportunistic or helminthic infections despite infection resolution or otherwise recurrent infections of abnormal frequency or prolonged duration History of moderate-to-severe congestive heart failure (NYHA Class III or IV), recent cerebrovascular accident, or any other condition in the opinion of the Investigator that would put the participant at risk by participation in the protocol History of solid organ transplant History of alcohol or drug abuse within the past 2 years History of diagnosis of demyelinating disease such as but not limited to: Multiple Sclerosis Acute Disseminated Encephalomyelitis Balo's Disease (Concentric Sclerosis) Charcot-Marie-Tooth Disease Guillain-Barre Syndrome human T-lymphotropic virus 1 Associated Myelopathy Neuromyelitis Optica (Devic's Disease) Planned surgery during the treatment period Participants who are Steinbrocker class IV functional capacity (incapacitated, largely or wholly bed-ridden or confined to a wheelchair, with little or no self-care) Vaccination with live or live-attenuated virus vaccine within 6 weeks prior to randomization or plan to receive one during the trial Any non-live vaccine (eg, COVID-19) within 14 days prior to randomization or plan to receive one during the trial Participant with personal or family history of long QT syndrome Active malignancy, lymphoproliferative disease, or malignancy in remission for less than 5 years, except adequately treated (cured) localized carcinoma in situ of the cervix or ductal breast, or squamous cell carcinoma, or basal cell carcinoma of the skin Previous or current use of biologic therapy or targeted synthetic disease modifying anti-rheumatic drugs (tsDMARD - such as JAK inhibitors) for RA Use of oral glucocorticoid greater than prednisone 10 mg per day or equivalent per day, or a change in dosage within 4 weeks prior to screening. The dose of oral glucocorticoid must remain stable. Use of parenteral glucocorticoids or intra-articular glucocorticoids within 4 weeks prior to screening Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) within 1 week prior to screening Prior use of conventional disease-modifying anti-rheumatic drugs (cDMARDs) other than MTX The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR441566 dose regimen A<br>Participant will receive dose regimen A of SAR441566 for 12 weeks | Drug: SAR441566<br>* Tablet<br>|
| Experimental: SAR441566 dose regimen B<br>Participant will receive dose regimen B of SAR441566 for 12 weeks | Drug: SAR441566<br>* Tablet<br>|
| Experimental: SAR441566 dose regimen C<br>Participant will receive dose regimen C of SAR441566 for 12 weeks | Drug: SAR441566<br>* Tablet<br>|
| Experimental: SAR441566 dose regimen D<br>Participant will receive dose regimen D of SAR441566 for 12 weeks | Drug: SAR441566<br>* Tablet<br>|
| Placebo Comparator: Placebo<br>Participant will receive SAR441566-matching placebo for 12 weeks | Drug: Placebo<br>* Tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving at least 20% improvement from baseline in the American College of Rheumatology (ACR) score at week 12 | ACR20 response criteria is a dichotomous composite endpoint indicating the proportion of participants with at least 20 percent improvement in the number of tender and swollen joints, and in three out of the remaining five ACR core-set measures: patient pain (VAS, No pain to Severe Pain), Patient Global Assessment of disease activity (VAS, Very well to Very Poor), physician global assessment of disease activity (VAS, Very good to Very bad), physical functioning assessment (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and acute phase reactants (ESR or CRP mg/dl; in this study CRP will be used). ACR response is scored as a percentage improvement, comparing disease activity at two discrete time points. ACR20 is ≥ 20% improvement. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Disease activity score - C-reactive protein (DAS-28 CRP) at week 12 | The DAS28-CRP is a composite endpoint. DAS28-CRP is comprised of clinical assessment of 28 swollen joint count (SJC)/ tender joint count (TJC), patient assessment of global disease activity and CRP mg/dL. It is a continuous measure allowing for measurement of absolute change in disease burden and percentage improvement. The DAS28 can be calculated using the following formula: DAS28 = 0.56 x 28TJC + 0.28 x 28SJC + 0.36 x Log(CRP+1) + 0.014 x GH + 0.96 The DAS28 provides a number indicating the current activity of the RA. A DAS28 above 5.1 means high disease activity, whereas a DAS28 below 3.2 indicates low disease activity and a DAS28 below 2.6 means disease remission. | Baseline to Week 12 | 
| Proportion of participants achieving at least 50% improvement from baseline in the ACR score at week 12 | ACR response is scored as a percentage improvement, comparing disease activity at two discrete time points. ACR50 is ≥ 50% improvement. ACR50 responders include ACR20 responders | Baseline to week 12 | 
| Number of participants with Treatment-Emergent Adverse Events (TEAEs), serious AEs (SAEs), and AEs of special interest (AESIs) | Incidence of TEAEs, SAEs, and AESIs | Baseline to week 14 | 
| Plasma pre-dose concentrations of SAR441566 |  | Week 2 to week 12 | 
| Plasma post-dose concentrations of SAR441566 |  | Week 0 to week 12 |