Inclusion Criteria:

• AD as defined by the American Academy of Dermatology Consensus Criteria.
• History of AD for at least 12 months prior to baseline as determined by the Investigator through patient interview.
• Eczema Area and Severity Index (EASI) score ≥ 12 at screening and at baseline.
• IGA score ≥ 3 (on the 0 to 4 IGA scale) at baseline.
• BSA of AD involvement ≥ 10% at baseline.
• Documented inadequate response or intolerance to TCS within 6 months prior to baseline visit
• Baseline PP-NRS score for maximum itch intensity ≥4.
• All contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• For optional substudy only: Willingness to have 2 tape strips for comparison of baseline and treatment response.

Exclusion Criteria:

• Skin comorbidities that may interfere with study assessments such as psoriasis, tinea corporis, lupus erythematosus.
• Conditions that may predispose the patient to excessive bleeding.
• Any other clinically significant disease, condition, or medical history that, in the opinion of the Investigator, would interfere with participant safety, trial evaluations, and/or trial procedures.
• Laboratory abnormalities at the screening visit
• History of serious infections requiring intravenous therapy with the potential for recurrence (as judged by the Site Investigator and the Sponsor Medical Monitor), with less than 4 weeks interval between resolution of serious infection and first dose of study drug, or currently active moderate to severe infection at Screening (Grade 2 or higher) including active coronavirus disease 2019 (COVID-19).
• Live vaccine except Bacille Calmette Guerin-vaccination within 28 days prior to Day 1 or plan to receive one during the trial; Bacille Calmette Guerin-vaccination within 12 months prior to Screening.
• COVID-19 vaccine within 14 days prior to Study Day 1.
• Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate rilzabrutinib/placebo absorption.
• Initiation of prescription moisturizers (with or without additives such as ceramide, hyaluronic acid, urea, or filaggrin), topical anesthetics or antihistamines during the screening period.
• Use of TCS, topical calcineurin (tacrolimus, and/or pimecrolimus) or topical phosphodiesterase 4 inhibitor within 1 week prior to baseline and as concomitant medication.
• Use of systemic corticosteroids within 4 weeks prior to baseline and as concomitant medication.
• Phototherapy for AD or regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks prior to baseline or likely to be required as concomitant procedure during the study.
• Use of mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, dapsone, intravenous immunoglobulin (IVIG), Kineret (anakinra), Enbrel (etanercept), or any other immunosuppressant not mentioned in this exclusion criterion within 4 weeks prior to baseline.
• Use of infliximab, adalimumab, golimumab, abatacept, tocilizumab, certolizumab, secukinumab, IFN-γ, JAK inhibitors, dupilumab, and any other biologic or targeted-synthetic disease modifier drug not mentioned in this exclusion criterion or in exclusion criterion, as well as plasmapheresis within 12 weeks prior to baseline.
• Use of anti-CD20 drugs such as rituximab, ofatumumab, other long-acting biologics within 6 months prior to baseline (or shorter if there is documented B cell reconstitution for anti-CD20 drugs).
• Use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 3 days of baseline (it is acceptable to change participant to H2 receptor blocking drugs prior to baseline).
• Concomitant use of known systemic strong-to-moderate inhibitors and inducers of cytochrome P450 3A (CYP3A) within 14 days or 5 half-lives (whichever is longer) prior to baseline.
• Previous use of a BTK inhibitor.
• Had received any investigational drug (or is currently using an investigational device) within the 30 days before baseline, or at least 5 times the respective elimination half-life time (whichever is longer).
• Active TB or a history of incompletely treated TB, Quantiferon positive patients, Clinically significant abnormality consistent with prior/active TB infection based upon chest radiograph with at least posterior-anterior view, Suspected extrapulmonary TB infection, or patients at high risk of contracting TB.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.