This study will assess the efficacy and safety of tocilizumab compared with placebo in participants with SSc across approximately 120 planned global study sites. The study will consist of a 48-week, double-blind, placebo-controlled period followed by a 48-week open-label treatment period. Participants will be assigned, in a 1:1 ratio, to double-blind treatment with active tocilizumab or matching placebo. In the open-label period, eligible participants from either arm may receive active tocilizumab.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
212
Participants will receive matching placebo subcutaneous (SC) injections once weekly for 48 weeks of double-blind treatment.
Participants will receive 162 mg SC tocilizumab once weekly for 48 weeks of double-blind treatment. The same regimen will be given to all eligible participants for 48 weeks of open-label treatment.
Change in Modified Rodnan Skin Score (mRSS) During Double-blind Period
The efficacy of TCZ vs placebo is evaluated in terms of in mean change in mRSS. Skin thickness will be assessed by palpation and rated using an mRSS that ranges from 0 (normal) to 3 (severe skin thickening) across 17 different body sites. The total score is the sum of the individual skin scores from all of these sites and ranges from 0 to 51 units.
Time frame: From baseline to week 48
Percentage of Participants With Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS During Double-blind Period
The proportion of participants with threshold improvements in mRSS at Week 48 relative to baseline.
Time frame: From Baseline to Week 48
Change From Baseline in Percent Predicted FVC (ppFVC) During Double-blind Period
FVC is pulmonary function test and will be conducted as per the study Pulmonary Function Manual, which is based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. Patients perform three to eight exhalations into a spirometer with the highest value recorded.
Time frame: Baseline to week 48
Change in Forced Vital Capacity (FVC) During Double-blind Period
FVC is pulmonary function test and will be conducted as per the study Pulmonary Function Manual, which is based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. Patients perform three to eight exhalations into a spirometer with the highest value recorded.
Time frame: From Baseline to Week 48
Change in Health Assessment Questionnaire Disability Index (HAQ-DI) Score During Double-blind Period
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TriWest Research Associates, LLC
El Cajon, California, United States
St. Joseph's Heritage Healthcare
Fullerton, California, United States
Univ of Calif., Los Angeles; Rheumatology
Los Angeles, California, United States
Arthritis Associates of Southern California
Los Angeles, California, United States
Georgetown Uni. Hosp.; Rheumatology, Immunology and Allergy Dept.
Washington D.C., District of Columbia, United States
Rheumatology Assoc. of S. Florida - Clinical Research Center
Boca Raton, Florida, United States
Millenium Research
Ormond Beach, Florida, United States
Boston Univ Med Center - AC
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
West Michigan Rheumatology, PLLC
Grand Rapids, Michigan, United States
...and 73 more locations
The Health Assessment Questionnaire Disability Index (HAQ-DI) consists of 20 questions referring to eight component sets consisting of dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item is scored on a 4-point scale from 0 to 3: 0 = Without any difficulty; 1 = With some difficulty; 2 = With much difficulty; 3 = Unable to do. Overall score was computed as the sum of component set scores and divided by the number of component sets answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. The total score indicates the patient's self-assessed level of disability. This outcome measure represents the change in mean score from baseline. A negative change from baseline indicates improvement.
Time frame: From Baseline to Week 48
Change in Patient Global Assessment Score During Double-blind Period
The Patient's Global Assessment represents the patient's overall assessment of current SSc status on a 100-mm horizontal visual analogue scale (VAS), ranging from 0 on the extreme left end of the scale indicating "has no effect at all" (symptom free), and 100 on the extreme right end indicating "worst possible effect."
Time frame: From Baseline to Week 48
Change in Physician Global Assessment Score During Double-blind Period
The Physician's Global Assessment is to be completed on the basis of examination and overall assessment of the patient. The physician's assessment of the patient's SSc status will be scored on a 100-mm horizontal visual analogue scale (VAS), ranging from 0 on the extreme left end of the scale indicating "has no effect at all" (symptom free), and 100 on the extreme right end indicating "worst possible effect."
Time frame: From Baseline to Week 48
Time to Treatment Failure According to mRSS, FVC, or Protocol-Specified Event During Double-blind Period
Time to treatment failure is defined as the time from randomization to the time of death, decline in percent-predicted FVC \> 10% relative to baseline, \> 20% increase in mRSS and an increase in mRSS of equal to or more than 5 points, or occurrence of a predefined SSc-related complication as adjudicated by the Clinical Adjudication Committee (whichever occurs first) during the 48-week double-blind treatment period. The median TTF was not estimable and is not presented for either treatment arm because of the low number of patients with events at Week 48.
Time frame: From Baseline to Week 48
Summary of Adverse Events During Double-blind Period
Summary of key safety results including Adverse Events of Special Interest (AESI). All adverse events categorized according to MedDRA version 20.1. NMSC = Non-Melanoma Skin Cancer
Time frame: From Baseline until Week 48
Incidence and Severity of Adverse Events During Double-blind Period
Adverse events listed according to MedDRA version 20.1 preferred terms and severity grade.
Time frame: From Baseline until Week 48
Number of Participants With Adverse Events Leading to Death During Double-blind Period
Reason of death is coded using MedDRA 20.1
Time frame: From Baseline up to Week 48
Frequency of Serious Systemic Sclerosis (SSC) Related Complications During Double-blind Period
Adverse event terms coded using MedDRA 20.1. Includes only those serious events adjudicated as SSC-related complications by an independent external committee.
Time frame: From Baseline up to Week 48
Incidence of Haematology and Hepatic Laboratory Parameters During Double-blind Period
A laboratory event occurred if the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade for a post-baseline laboratory measurement increased from baseline.
Time frame: From Baseline up to Week 48
Percentage of Participants With Change in Digital Ulcer Count During Double-blind Period
A digital ulcer is defined as an ulcer at or distal to the MCP joint on either the dorsal or volar surface, with loss of surface epithelialization. This does not include fissures, cracks, or calcium extrusions from calcinosis cutis. The number of fingers (0-10) with digital ulcers and the number of digital (or finger) ulcers will be counted and recorded by the investigator.
Time frame: From Baseline to Week 48
Percentage of Participants With Positive Anti-Tocilizumab Assay Result at Baseline
Incidence of anti-Tocilizumab at baseline
Time frame: Baseline
Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline up to Week 48
Incidence of anti-Tocilizumab antibodies during the study relative to the prevalence of anti-Tocilizumab antibodies at baseline. Samples that are positive for anti-TCZ in the screening assay will be further analyzed by a confirmation assay to confirm specificity. If the confirmation assay is positive, two additional tests will be performed: a neutralizing assay for the ability to inhibit the activity of TCZ and a test for anti -TCZ of the IgE isotype.
Time frame: Double-blind period (up to Week 48)
Correlation Between Anti-Tocilizumab Antibody Status and Outcome Measures Pertaining to the Efficacy, Safety, and Pharmacokinetics of Tocilizumab
Pre-specified analysis of the relationship between Anti-Tocilizumab Antibody status and safety, efficacy, and PK endpoints were not analyzed via subgroup analyses as there was only 1 patient with ADA-positive status.
Time frame: Baseline; during Weeks 8, 16, 24, 36, 48, 96, and/or at treatment discontinuation (up to 96 weeks); and 8 weeks after treatment discontinuation (up to 104 weeks overall)
Erythrocyte Sedimentation Rate (ESR), Mean, From Baseline to Week 48
Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Predose up to Week 48
Erythrocyte Sedimentation Rate (ESR), Median, From Baseline to Week 48
Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 48
Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum Interleukin (IL)-6 Level, Median, From Baseline to Week 48
Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum Interleukin (IL)-6 Level, Mean Change From Baseline to Week 48
Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum Interleukin (IL)-6 Level, Median Change From Baseline to Week 48
Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, From Baseline to Week 48
Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum Soluble Interleukin (IL)-6 Receptor Level, Median, From Baseline to Week 48
Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum Soluble Interleukin (IL)-6 Receptor Level, Mean Change From Baseline to Week 48
Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum Soluble Interleukin (IL)-6 Receptor Level, Median Change From Baseline to Week 48
Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline to Week 48
Serum C-Reactive Protein (CRP) Level, Mean, From Baseline to Week 48
Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline up to Week 48
Serum C-Reactive Protein (CRP) Level, Median, From Baseline to Week 48
Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline up to Week 48
Serum Tocilizumab Concentration, Mean, From Baseline to Week 48
Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Time frame: From Baseline to Week 48
Serum Tocilizumab Concentration, Median, From Baseline to Week 48
Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Time frame: From Baseline to Week 48
Correlation Between Low Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Correlation Between Low Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Correlation Between Medium Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Correlation Between Medium Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Correlation Between High Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Correlation Between High Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Change in Mean Modified Rodnan Skin Score (mRSS) at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Change in Median Modified Rodnan Skin Score (mRSS), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Change in Mean Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
In order to characterize exposure-efficacy relationships, ppFVC scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Change in Median Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
In order to characterize exposure-efficacy relationships, ppFVC scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Time frame: From Baseline to Week 48
Summary of Adverse Events Up to Week 96
Summary of key safety results including Adverse Events of Special Interest (AESI). All adverse events categorized according to MedDRA version 21.1. NMSC = Non-Melanoma Skin Cancer
Time frame: Up to Week 96
Incidence and Severity of Adverse Events Up to Week 96
Adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) severity grade: 1 = mild, 2 = moderate, 3 = severe and/or requiring medical intervention but not life-threatening, 4 = life-threatening consequences, and 5 = death.
Time frame: Up to Week 96
Number of Participants With Adverse Events Leading to Death Up to Week 96
Time frame: Up to Week 96
Percentage of Participants With Change in Digital Ulcer Count at Week 96
A digital ulcer is defined as an ulcer at or distal to the MCP joint on either the dorsal or volar surface, with loss of surface epithelialization. This does not include fissures, cracks, or calcium extrusions from calcinosis cutis. The number of fingers (0-10) with digital ulcers and the number of digital (or finger) ulcers will be counted and recorded by the investigator.
Time frame: From Baseline to Week 96
Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline From Week 48 to 96
Reported were the percentage of participants with post-baseline treatment-induced anti-TCZ antibodies. Positive samples underwent additional analyses: a neutralizing assay for the ability to inhibit the activity of TCZ and a test for anti -TCZ of the IgE isotype.
Time frame: Open-label period from Week 48 to 96
Erythrocyte Sedimentation Rate (ESR) Up to Week 96
Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: Up to Week 96
Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 96
Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: Up to Week 96
Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, Up to Week 96
Serum Soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: Up to Week 96
Serum C-Reactive Protein (CRP) Level, Mean, Up to Week 96
Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Time frame: From Baseline up to Week 96
Serum Tocilizumab Concentration, Mean, Up to Week 96
Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Time frame: Up to Week 96