Effectiveness and Safety of SAR156597 in Treating Diffuse Systemic Sclerosis

Study Overview
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Brief Summary
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Primary Objective: To evaluate, in comparison with placebo, the efficacy of SAR156597 administered subcutaneously for 24 weeks on skin fibrosis in participants with diffuse cutaneous systemic sclerosis (dcSSc). Secondary Objectives: To evaluate the efficacy of SAR156597 compared to placebo on physical/functional disability in participants with dcSSc. To evaluate the efficacy of SAR156597 compared to placebo on respiratory function of participants with dcSSc. To evaluate the safety profile of SAR156597 compared to placebo in participants with dcSSc. To evaluate the potential for immunogenicity (anti-drug antibodies response) of SAR156597 in participants with dcSSc. To evaluate the pharmacokinetics (trough plasma concentrations) of SAR156597 administered subcutaneously for 24 weeks.

Detailed Description
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The total study duration per participant was 39 weeks; consisting of a 4-week screening, a 24-week of study treatment period, and an 11-week follow-up with no study drug treatment.

Official Title
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Efficacy and Safety of SAR156597 in the Treatment of Diffuse Cutaneous Systemic Sclerosis (dcSSc): A Randomized, Double-blind, Placebo-controlled, 24-week, Proof of Concept Study

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: SAR156597
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Systemic Sclerosis (SSc) according to the American College of Rheumatology/The European League against Rheumatism (ACR/EULAR) 2013 criteria. Diffused cutaneous form of SSc according to Leroy's criteria. Able and willing to sign the written informed consent form with comprehension of its contents and complied with the requirements of the study protocol. Exclusion criteria: Aged less than (<) 18 years of age. Disease duration for greater than (>) 36 months from time of first non-Raynaud's phenomenon manifestation. Modified Rodnan Skin Score <10 or >35 at screening and baseline visits. History of vasculitis, active or in remission. Diagnosis of connective tissue diseases (other than SSc) or overlap syndrome (eg, polymyositis/scleroderma). Positive Human Immunodeficiency Virus (HIV) serology or a known history of HIV infection, active or in remission. Abnormal hepatitis B and/or hepatitis C tests indicative of active or chronic infection: Abnormal Hepatitis B tests: Positive hepatitis B surface antigen (HBsAg) OR positive total hepatitis B core antibody (HBcAb) with negative hepatitis B surface antibody (HBsAb) OR positive total HBcAb with positive HBsAb and presence of hepatitis B virus deoxyribonucleic acid. Abnormal Hepatitis C tests: Positive anti-hepatitis C virus antibody (HCV Ab) and positive HCV ribonucleic acid. Positive or 2 confirmed indeterminate Quantiferon-tuberculosis Gold tests at screening (regardless of prior treatment status). Serious infection (eg, pneumonia, pyelonephritis) within 4 weeks of screening, infection requiring hospitalization or intravenous antibiotics within 4 weeks of screening or chronic bacterial infection (eg, osteomyelitis). History of anaphylaxis to any biologic therapy. Evidence of any clinically significant, severe or unstable, acute or chronically progressive, uncontrolled infection or medical condition (eg, cerebral, cardiac, pulmonary, renal, hepatic, gastrointestinal or neurologic other than SSc or SSc-interstitial lung disease) or previous, active or pending surgical disorder, or any condition that may affect participant safety in the judgment of the Investigator. At screening, the percent (%) predicted forced vital capacity was less than or equal to (<=75) % and % predicted carbon monoxide diffusing lung capacity after hemoglobin correction is <=40%. History of heart failure (including acutely decompensated in the setting of preserved ejection fraction), left ventricular ejection fraction <= 45%, coronary artery disease, angina, myocardial infarction, ischemic cardiomyopathy and/or hypertrophic cardiomyopathy. Any prior history of malignancy or active malignancy, including lymphoproliferative diseases (except successfully-treated carcinoma in-situ of the cervix, non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin) within 5 years prior to baseline. Ischemic electrocardiogram (ECG) changes (except those not supported by the findings of a left heart catheterization performed in the last year) and/or other clinically significant ECG findings. (All abnormal ECG finding were reviewed and confirmed by a local cardiologist). High dose steroids (>10 mg/day prednisolone equivalent); or change in steroid dose within 4 weeks prior to randomization (or baseline visit); or expected changes during the course of the study. Previous treatment with rituximab within 12 months prior to screening. Previous treatment with bone marrow transplantation, total lymphoid irradiation or ablative ultra-high dose cyclophosphamide. Treatment with high dose immunosuppressive drug (eg, cyclophosphamide >1 mg/kilogram (kg) oral/day or >750 mg intravenous (IV)/month; azathioprine >100 mg/day; methotrexate >15 mg/week; mycophenolate mofetil >2 gram (g)/day) within 3 months of screening or change in dose within 4 weeks prior to randomization (or baseline visit); or expected changes in dose during the course of the study. Treatment with etanercept, cyclosporine A, IV immunoglobulin, rapamycin, D-penicillamine, tyrosine kinase inhibitors within 4 weeks of screening or antithymocyte globulin within 6 months of screening. Treatment with infliximab, certolizumab, golimumab, abatacept, or adalimumab, tocilizumab within 8 weeks of screening or anakinra within 1 week of screening. Treatment with any investigational drug within 1 month of screening, or 5 half-lives, if known (whichever was longer). Abnormal laboratory tests at screening: Alanine transaminase or aspartate transaminase >2 times upper limit of normal range; Hemoglobin <11 g/100 milliliter (mL) for male and <10 g/100 mL for female; Neutrophils <1500/mm^3 (except <1000/mm^3 for those of African descent); Platelets <100 000/mm^3; Creatinine greater than or equal to (>=)150 micromole/Liter (mcgmol/L). Current history of substance and/or alcohol abuse. Any condition or circumstance that would preclude the participant from following and completing protocol requirements, in the opinion of the Investigator. Pregnant or breastfeeding woman. Women who were of childbearing potential not protected by highly-effective contraceptive method(s) of birth control, and/or who were unwilling or unable to be tested for pregnancy. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (for SAR156597), single subcutaneous (SC) injection once in a week (QW) up to Week 24. | Drug: Placebo<br>* Pharmaceutical form: Solution Route of administration: Subcutaneous<br>|
| Experimental: SAR156597<br>SAR156597 200 milligram (mg), single SC injection QW up to Week 24. | Drug: SAR156597<br>* Pharmaceutical form: Solution Route of administration: Subcutaneous<br>* Other names: Romilkimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Modified Rodnan Skin Score to Week 24 | mRSS, an accepted clinical measure of the skin thickness (fibrosis). Investigator physicians or qualified medical personnel assessed the thickening of skin in 17 skin sites including fingers, hands, forearms, arms, feet, legs and thighs, face, chest and abdomen. Each skin site was rated on a 0-3 scale; where 0 = normal skin, 1 = mild thickness, 2 = moderate thickness and 3 = severe thickness. Total mRSS ranged from 0 (no thickening) to 51 (severe thickening in all 17 areas), where higher score indicated more severity of skin thickening/worst outcome. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 24 | HAQ-DI assessed the degree of difficulty participants experienced in 8 daily living activity domains during past week: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each activity category consisted of 2-3 items. For each items, level of difficulty was scored from 0-3 (0=no difficulty, 1=some difficulty, 2=much difficulty, 3=unable to do). Overall HAQ-DI score was computed as the sum of domain scores divided by the number of domains answered, providing a score from 0 (no difficulty) to 3 (maximum difficulty), where higher score indicated greater disability. | Baseline, Week 24 | 
| Change From Baseline in Mean Observed Forced Vital Capacity (FVC) Level to Week 24 | FVC was the total amount of air (in liters) exhaled from the lungs during the lung function test measured by spirometer which assessed the change in lung function related to the disease status of an underlying ILD. Change from Baseline was calculated by subtracting Baseline value from Week 24 value. | Baseline, Week 24 | 
| Change From Baseline in Mean Observed Diffusing Lung Capacity for Carbon Monoxide (DLco) to Week 24 | DLco is a measurement of the ability of the lungs to transfer gases from the air to the blood. Participant breathe in (inhale) air containing a very small, harmless amount of a tracer gas, such as carbon monoxide. Participant hold the breath for 10 seconds, then rapidly blow it out (exhale). The exhaled gas was tested to determine amount of the tracer gas absorbed during the breath. | Baseline, Week 24 |