Systemic Sclerosis
Conditions
Brief summary
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
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.
Interventions
DRUGSAR156597
Pharmaceutical form: Solution Route of administration: Subcutaneous
DRUGPlacebo
Pharmaceutical form: Solution Route of administration: Subcutaneous
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Rodnan Skin Score to Week 24 | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 24 | Baseline, 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. |
| Change From Baseline in Mean Observed Forced Vital Capacity (FVC) Level to Week 24 | Baseline, 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. |
| Change From Baseline in Mean Observed Diffusing Lung Capacity for Carbon Monoxide (DLco) to Week 24 | Baseline, 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. |
Countries
Argentina, Belgium, Estonia, France, Germany, Italy, Mexico, Poland, Romania, Russia, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in 13 countries. A total of 97 participants were involved in the study from 21 December 2016 to 01 April 2019.
Pre-assignment details
Participants were randomized in 1:1 ratio (placebo and SAR156597). Randomization was stratified based upon the participant's medical history of systemic sclerosis (SSc) associated interstitial lung disease (SSc-ILD) (yes or no). Assignment was done by Interactive Voice Response System (IVRS).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo (for SAR156597), single SC injection QW up to Week 24. | 49 |
| SAR156597 SAR156597 200 mg, single SC injection QW up to Week 24. | 48 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lack of Efficacy | 3 | 1 |
| Overall Study | Other than specified above | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | SAR156597 | Total |
|---|---|---|---|
| Age, Continuous | 47.2 years STANDARD_DEVIATION 12.1 | 52.3 years STANDARD_DEVIATION 10.8 | 49.7 years STANDARD_DEVIATION 11.7 |
| Modified Rodnan Skin Score (mRSS) | 20.6 units on a scale STANDARD_DEVIATION 7 | 20.5 units on a scale STANDARD_DEVIATION 6.1 | 20.6 units on a scale STANDARD_DEVIATION 6.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 45 Participants | 45 Participants | 90 Participants |
| Sex: Female, Male Female | 38 Participants | 39 Participants | 77 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 49 | 1 / 48 |
| other Total, other adverse events | 27 / 49 | 31 / 48 |
| serious Total, serious adverse events | 5 / 49 | 4 / 48 |
Outcome results
Primary
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.
Time frame: Baseline, Week 24
Population: Analysis was performed on the intent to treat (ITT) population which included all randomized participants and were analyzed according to the treatment group allocated by randomization. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Modified Rodnan Skin Score to Week 24 | -2.45 score on a scale | Standard Error 0.85 |
| SAR156597 | Change From Baseline in Modified Rodnan Skin Score to Week 24 | -4.76 score on a scale | Standard Error 0.86 |
Comparison: Analysis was performed using mixed model repeated measures (MMRM) model. The model included fixed categorical effects of treatment group, randomization strata as per IVRS, timepoint, treatment-by-timepoint and strata-by-timepoint interactions, as well as the continuous fixed covariate of baseline and baseline-by-timepoint interactions.p-value: 0.029195% CI: [-4.71, 0.08]Mixed-effect model with repeated measure
Secondary
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.
Time frame: Baseline, Week 24
Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 24 | -0.12 score on a scale | Standard Error 0.08 |
| SAR156597 | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 24 | -0.09 score on a scale | Standard Error 0.08 |
Secondary
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.
Time frame: Baseline, Week 24
Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Observed Diffusing Lung Capacity for Carbon Monoxide (DLco) to Week 24 | -0.27 millimoles per minute per kilopascal | Standard Error 0.1 |
| SAR156597 | Change From Baseline in Mean Observed Diffusing Lung Capacity for Carbon Monoxide (DLco) to Week 24 | -0.12 millimoles per minute per kilopascal | Standard Error 0.1 |
Secondary
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.
Time frame: Baseline, Week 24
Population: Analysis was performed on the ITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Observed Forced Vital Capacity (FVC) Level to Week 24 | -0.08 liters | Standard Error 0.04 |
| SAR156597 | Change From Baseline in Mean Observed Forced Vital Capacity (FVC) Level to Week 24 | -0.01 liters | Standard Error 0.04 |