Effectiveness and Safety of SAR156597 in Treating Diffuse Systemic Sclerosis

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

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.

Study Overview

• Status: Completed
• Conditions: Systemic Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: SAR156597

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1015ABO
    • Investigational Site Number 0320003
  • Caba, Argentina, C1181ACH
    • Investigational Site Number 0320002
  • Capital Federal, Argentina, C1280AEB
    • Investigational Site Number 0320005
  • San Miguel De Tucuman, Argentina, T4000AXL
    • Investigational Site Number 0320001
• Belgium
  • Gent, Belgium, 9000
    • Investigational Site Number 0560001
  • Leuven, Belgium, 3000
    • Investigational Site Number 0560002
• Estonia
  • Tallinn, Estonia, 13419
    • Investigational Site Number 2330001
• France
  • Montpellier, France, 34295
    • Investigational Site Number 2500003
  • Paris Cedex 14, France, 75014
    • Investigational Site Number 2500004
  • Strasbourg Cedex, France, 67098
    • Investigational Site Number 2500002
• Germany
  • Bad Nauheim, Germany, 61231
    • Investigational Site Number 2760003
  • Berlin, Germany, 10117
    • Investigational Site Number 2760001
  • Köln, Germany, 50937
    • Investigational Site Number 2760002
  • Ulm, Germany, 89081
    • Investigational Site Number 2760004
• Italy
  • Genova, Italy, 16132
    • Investigational site number 3800004
  • Milano, Italy, 20122
    • Investigational Site Number 3800001
  • Milano, Italy, 20122
    • Investigational Site Number 3800005
  • Orbassano, Italy, 10043
    • Investigational Site Number 3800006
• Mexico
  • Chihuahua, Mexico, 31000
    • Investigational Site Number 4840001
  • Guadalajara, Mexico, 44160
    • Investigational Site Number 4840005
  • Guadalajara, Mexico, 44690
    • Investigational Site Number 4840002
  • Monterrey, Mexico, 64460
    • Investigational Site Number 4840003
• Poland
  • Poznan, Poland, 61-397
    • Investigational Site Number 6160001
  • Warszawa, Poland, 02-691
    • Investigational Site Number 6160002
  • Wroclaw, Poland, 52-416
    • Investigational Site Number 6160003
• Romania
  • Bucharest, Romania, 011172
    • Investigational Site Number 6420003
  • Bucharest, Romania, 011172
    • Investigational Site Number 6420004
  • Bucuresti, Romania, 020475
    • Investigational Site Number 6420005
  • Cluj Napoca, Romania, 400006
    • Investigational Site Number 6420001
  • Targu Mures, Romania, 540142
    • Investigational Site Number 6420002
• Russian Federation
  • Kemerovo, Russian Federation, 650000
    • Investigational Site Number 6430002
  • Moscow, Russian Federation, 115404
    • Investigational Site Number 6430005
  • Moscow, Russian Federation, 115522
    • Investigational Site Number 6430001
  • Moscow, Russian Federation, 125284
    • Investigational Site Number 6430004
  • Ufa, Russian Federation, 450005
    • Investigational Site Number 6430003
• Ukraine
  • Kyiv, Ukraine, 02125
    • Investigational Site Number 8040001
  • Kyiv, Ukraine, 03151
    • Investigational Site Number 8040002
  • Kyiv, Ukraine, 04050
    • Investigational Site Number 8040004
  • Kyiv, Ukraine, 04070
    • Investigational Site Number 8040003
• United Kingdom
  • London, United Kingdom
    • Investigational Site Number 8260001
• United States
  • California
    • San Francisco, California, United States, 94143
      • Investigational Site Number 8400006
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Investigational Site Number 8400005
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Investigational Site Number 8400002
  • Texas
    • Houston, Texas, United States, 77030
      • Investigational Site Number 8400007

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo (for SAR156597), single subcutaneous (SC) injection once in a week (QW) up to Week 24.	Drug: Placebo; Pharmaceutical form: Solution Route of administration: Subcutaneous
Experimental: SAR156597; SAR156597 200 milligram (mg), single SC injection QW up to Week 24.	Drug: SAR156597; Pharmaceutical form: Solution Route of administration: Subcutaneous; Other Names: Romilkimab

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Allanore Y, Wung P, Soubrane C, Esperet C, Marrache F, Bejuit R, Lahmar A, Khanna D, Denton CP; Investigators. A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2020 Dec;79(12):1600-1607. doi: 10.1136/annrheumdis-2020-218447. Epub 2020 Sep 22.

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2016
• Primary Completion (Actual): January 14, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: September 30, 2016
• First Submitted That Met QC Criteria: September 30, 2016
• First Posted (Estimate): October 3, 2016

Study Record Updates

• Last Update Posted (Actual): March 21, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse
• Other Study ID Numbers: ACT14604; 2016-001028-80 (EudraCT Number); U1111-1179-4690 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No