Safety, Tolerability, Pharmacokinetics, and Therapeutic Efficacy of SAR441344 in Primary Sjögren's Syndrome (pSjS)

Study Overview
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Brief Summary
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Primary Objective: To evaluate the therapeutic efficacy of one dose level of SAR441344 versus placebo over 12 weeks in adult patients with primary Sjögren's syndrome (pSjS), assessed by the change of the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) Secondary Objectives: To evaluate the therapeutic efficacy of one dose level of SAR441344 versus placebo over 12 weeks in adult patients with pSjS To evaluate the therapeutic efficacy on fatigue of one dose level of SAR441344 versus placebo over 12 weeks in adult patients with pSjS To evaluate the pharmacokinetic (PK) exposure of one dose level of SAR441344 over 12 weeks in adult patients with pSjS To evaluate the safety and tolerability of one dose level of SAR441344 versus placebo in adult patients with pSjS as determined by adverse events (AEs) To evaluate the local tolerability of one dose level of SAR441344 versus placebo over 12 weeks in adult patients with pSjS To evaluate the safety and tolerability of one dose level of SAR441344 versus placebo over 12 weeks in adult patients with pSjS determined by electrocardiogram, vital signs, and laboratory evaluations To measure the immunogenicity of one dose level of SAR441344 versus placebo over 12 weeks in adult patients with pSjS This is a multicenter, randomized, double blind, placebo controlled, parallel group proof of concept Phase 2 study to evaluate the therapeutic efficacy of SAR441344 in adult patients with primary Sjögren's syndrome (pSjS), as well as safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Study visit frequency: every 2 weeks in the treatment period and every 4 weeks in the follow-up period. The total duration of the study will be 24 weeks (28 weeks including maximum screening duration) for each participant, including a 12-week treatment period and a 12-week follow-up period.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group Study of the Safety, Tolerability, Pharmacokinetics, and Therapeutic Efficacy of SAR441344 in Adult Patients With Primary Sjögren's Syndrome (pSjS)

Conditions
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Sjögren's Syndrome, Sjogren's Syndrome

Intervention / Treatment
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* Drug: SAR441344
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent. Diagnosis of pSjS according to the American College of Rheumatology/EULAR 2016 criteria at Screening. Disease duration since first diagnosis of pSjS ≤15 years based on medical history. Participants with moderate to severe disease activity set with ESSDAI total score ≥5, based on the following domains at Screening: glandular, articular, muscular, hematological, biological, and constitutional, lymphadenopathy. Seropositive for anti-Ro/SSA antibodies. IgG > lower limit of normal (ULN) at Screening. Stimulated salivary flow rate of ≥0.1 mL/min at Screening or Baseline. Body weight within 45 to 120 kg (inclusive) and body mass index within the range of 18.0 to 35.0 kg/m2 (inclusive) at Screening. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Capable of giving signed informed consent. Exclusion Criteria: Any autoimmune disease (except pSjS and Hashimoto thyroiditis) with or without secondary SjS. History, clinical evidence, suspicion or significant risk for thromboembolic events, as well as myocardial infarction, stroke, and/or antiphospholipid syndrome and any participants requiring antithrombotic treatment. Active life threatening or organ threatening complications of pSjS disease at the time of Screening based on treating physician evaluation including but not restricted to: Vasculitis with renal, digestive, cardiac, pulmonary, or CNS involvement characterized as severe, Active central nervous system (CNS) or peripheral nervous system (PNS) involvement requiring high dose steroids, Severe renal involvement defined by objective measures, Lymphoma. Cardiac heart failure Stage III or IV according to the New York Heart Association. Severe pulmonary impairment documented by an abnormal pulmonary function test. Serious systemic viral, bacterial or fungal infection (eg, pneumonia, pyelonephritis), infection requiring hospitalization or IV antibiotics or significant chronic viral (including history of recurrent or active herpes zoster), bacterial, or fungal infection (eg, osteomyelitis) 30 days before and during Screening. Participants with a history of invasive opportunistic infections, such as, but not limited to histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis jirovecii, and aspergillosis, regardless of resolution. Evidence of active or latent tuberculosis (TB) as documented by medical history (eg, chest X rays) and examination, and TB testing: A positive or 2 indeterminate QuantiFERON® TB Gold tests at Screening (regardless of prior treatment status). Evidence of any clinically significant, severe or unstable, acute or chronically progressive, uncontrolled infection or medical condition (eg, cerebral, cardiac, pulmonary, renal, hepatic, gastrointestinal, neurologic, or any known immune deficiency) or previous, active or pending surgical disorder, or any condition that may affect participant safety in the judgment of the Investigator (including vaccinations which are not updated based on local regulation). History or presence of diseases which exclude diagnosis of SjS as per the American College of Rheumatology/EULAR 2016 criteria including, but not limited to, sarcoidosis, amyloidosis, graft-versus-host disease, IgG4 related disease, and history of head and neck radiation treatment. History of systemic hypersensitivity reaction or significant allergies, other than localized injection site reaction, to any humanized monoclonal antibody. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis). Any prior history of malignancy or active malignancy, including lymphoproliferative diseases and lymphoma (except successfully treated carcinoma in situ of the cervix, nonmetastatic squamous cell or basal cell carcinoma of the skin) within 5 years prior to Baseline. Unstable dose of nonsteroidal anti inflammatory drugs (NSAIDs) and/or unstable use of topical and/or pharmacological stimulant treatment for salivary and lacrimal glands 4 weeks before Screening. High dose steroids, or a change in steroid dose within 4 weeks prior to Day 1/Randomization or expected changes during the course of the study. High dose of hydroxychloroquine or chloroquine, or methotrexate or change in hydroxychloroquine, chloroquine or methotrexate dose within 12 weeks prior to Day 1/Randomization or expected changes during the course of the study. Participants treated with the following medications/procedures prior to Screening: Previous treatment with azathioprine and other thiopurines, mycophenolate mofetil, sulfasalazine, or cyclosporine A within 3 months. Previous treatment with cyclophosphamide, leflunomide, or belimumab within 6 months. Previous treatment with rituximab within 12 months. Previous bone marrow transplantation, total lymphoid irradiation or ablative ultra high dose cyclophosphamide or IV Ig. Previous treatment with any other biologic drug within 5 times the half life of the drug. Received administration of any live (attenuated) vaccine within 3 months prior to Day 1/Randomization (eg, varicella zoster vaccine, oral polio, rabies). Clinically significant abnormal ECG or vital signs at Screening. Abnormal laboratory test(s) at Screening. Positive human immunodeficiency virus (HIV) serology (anti HIV1 and anti HIV2 antibodies) or a known history of HIV infection, active or in remission. Positive result on any of the following tests: hepatitis B surface antigen (HBsAg), anti hepatitis B core antibodies (anti HBc Ab), anti hepatitis C virus antibodies (HCV-Ab). If female, pregnant and/or breastfeeding. 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: SAR441344<br>SAR441344 single intravenous (IV) loading dose on Day 1 followed by a single subcutaneous (SC) dose administered once every 2 weeks from Week 2 to Week 10 (5 administrations) | Drug: SAR441344<br>* Pharmaceutical form: solution for injection Route of administration: intravenous or subcutaneous<br>|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Placebo<br>* Pharmaceutical form: solution for injection Route of administration: intravenous or subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ESSDAI | The ESSDAI is a validated and established outcome measurement for therapeutic efficacy in SjS, evaluating disease activity mainly on extra glandular manifestations. This score consists of 12 organ specific domains, which are scored based on organ specific items in 3 to 4 different severity grades. This score is summed up over all 12 domains in a weighted way to in a weighted way to summarize into a total score. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) | The ESSPRI is a validated and established outcome measurement, reported by patients, which rates the key disease manifestations fatigue, dryness, and pain based on a numeric scale ranging from 0 to 10, where 0 is defined as no symptoms and 10 as maximum imaginable complaints. | Baseline to Week 12 | 
| Change in the Multidimensional Fatigue Inventory (MFI) general fatigue subscale and other subscales | The MFI is a validated, 20 item self-report instrument to evaluate fatigue by investigating the following components: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. | Baseline to Week 12 | 
| Descriptive statistics of SAR441344 concentrations | Descriptive statistics of SAR441344 concentrations, including mean, median, and standard deviation, over 12 weeks. | Baseline to Week 12 | 
| Assessment of PK parameter: Cmax | Maximum plasma concentration of SAR441344 | Baseline to Week 12 | 
| Assessment of PK parameter: tmax | Time to reach Cmax for SAR441344 | Baseline to Week 12 | 
| Assessment of PK parameter: AUC0-tau | Area under the plasma concentration - time curve over the dosing interval | Baseline to Week 12 | 
| Assessment of PK parameter: t1/2z | Terminal half life of SAR441344 | Baseline to Week 12 | 
| Incidence of treatment emergent AEs (TEAEs), serious AEs (SAEs), and AEs of special interest (AESIs) |  | Baseline to Week 24 | 
| Incidence of study investigational medicinal product (IMP) discontinuation and withdrawals due to TEAEs |  | Baseline to Week 24 | 
| Change in participant reported local tolerability scale |  | Baseline to Week 12 | 
| Incidence of AEs related to local tolerability findings | Findings at the site of injection following IMP injection such as, but not limited to tenderness, erythema, and swelling will be recorded in the electronic case report form in 4 different grades (mild/moderate/severe/very severe). | Baseline to Week 12 | 
| Participants with medically significant changes in vital signs, electrocardiogram, and/or laboratory evaluations |  | Baseline to Week 12 | 
| Antidrug antibodies | Antidrug antibodies at Baseline, Week 4, Week 8, Week 12, and Week 24 | Baseline to Week 24 |