E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040767 |
E.1.2 | Term | Sjogren's syndrome |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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) |
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E.2.2 | Secondary objectives of the trial |
- 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
-Rheumatoid factor positive and/or IgG > upper 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 |
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E.4 | Principal exclusion criteria |
-Any autoimmune disease (except SjS 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 SjS 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 a systemic hypersensitivity reaction or significant allergies, other than localized injection site reaction, to 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 a change in hydroxychloroquine or chloroquine 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 within the given timeframe:
-Previous treatment with azathioprine and other thiopurines, methotrexate, 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1/ Change in 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.
2/ Change in 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.
3/ Descriptive statistics of SAR441344 concentrations: Descriptive statistics of SAR441344 concentrations, including mean, median, and standard deviation, over 12 weeks
4/ Assessment of PK parameter: Cmax: Maximum plasma concentration of SAR441344
5/ Assessment of PK parameter: tmax: Time to reach Cmax for SAR441344
6/ Assessment of PK parameter: AUC0-tau : Area under the plasma concentration - time curve over the dosing interval
7/ Assessment of PK parameter: t1/2z: Terminal half life of SAR441344
8/ Incidence of treatment emergent AEs (TEAEs), serious AEs (SAEs), and AEs of special interest (AESIs)
9/ Incidence of study investigational medicinal product (IMP) discontinuation and withdrawals due to TEAEs
10/ Change in participant reported local tolerability scale
11/ 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 e CRF in 4 different grades (mild/moderate/severe/very severe).
12/ Participants with medically significant changes in vital signs, electrocardiogram, and/or laboratory evaluations
13/ Antidrug antibodies: Antidrug antibodies at Baseline, Week 4, Week 8, Week 12, and Week 24 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From 1/ to 7/ and from 10/ to 12/ : Baseline to 12 weeks
8/, 9/, 13/: Baseline to Week 24
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Korea, Republic of |
Mexico |
Taiwan |
United States |
Belgium |
France |
Germany |
Hungary |
Netherlands |
Spain |
Argentina |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 5 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 5 |