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Completed

NCT Number: NCT02453256

A Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis (SSc)

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.

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Key information

Conditions

Systemic Sclerosis Connective Tissue Diseases Scleroderma, Systemic Skin Diseases Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Hospital Britanico; Haematology, Buenos Aires, Argentina

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Diagnosis of SSc according to American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria, meeting criteria for active disease and with total disease duration of less than or equal to (</=) 60 months
  • mRSS of 10-35 units, inclusive
  • Agreement to remain abstinent or use an effective contraceptive method among males and females with childbearing potential

Exclusion criteria

  • Pregnant or lactating females
  • Major surgery within 8 weeks prior to screening
  • Scleroderma limited to the face or areas distal to the elbows or knees
  • Rheumatic autoimmune disease other than SSc
  • Immunization with a live or attenuated vaccine within 4 weeks prior to Baseline
  • Known hypersensitivity to human, humanized, or murine monoclonal antibodies
  • Moderately severe nervous system, renal, endocrine, pulmonary, cardiovascular, or gastrointestinal (GI) disease not related to SSc, including diverticulitis or ulcerative lower GI disorders, or myocardial infarction (MI) within 6 months prior to screening
  • Active or significant history of infection, including treatment with intravenous (IV) antibiotics within 4 weeks or oral antibiotics within 2 weeks prior to screening
  • Significant history of tuberculosis (TB)
  • Primary or secondary immunodeficiency
  • Malignant disease, with the exception of excised/cured local basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix
  • History of drug or alcohol abuse

Treatment and study plan

Placebo

Drug

Participants will receive matching placebo subcutaneous (SC) injections once weekly for 48 weeks of double-blind treatment.

Tocilizumab

Drug

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.

Primary outcomes

  1. Change in Modified Rodnan Skin Score (mRSS) During Double-blind Period

    Time frame: From baseline to week 48

    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.

Secondary outcomes

  1. Percentage of Participants With Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS During Double-blind Period

    Time frame: From Baseline to Week 48

    The proportion of participants with threshold improvements in mRSS at Week 48 relative to baseline.

  2. Change From Baseline in Percent Predicted FVC (ppFVC) During Double-blind Period

    Time frame: Baseline to week 48

    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.

  3. Change in Forced Vital Capacity (FVC) During Double-blind Period

    Time frame: From Baseline to Week 48

    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.

  4. Change in Health Assessment Questionnaire Disability Index (HAQ-DI) Score During Double-blind Period

    Time frame: From Baseline to Week 48

    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.

  5. Change in Patient Global Assessment Score During Double-blind Period

    Time frame: From Baseline to Week 48

    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."

  6. Change in Physician Global Assessment Score During Double-blind Period

    Time frame: From Baseline to Week 48

    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."

  7. Time to Treatment Failure According to mRSS, FVC, or Protocol-Specified Event During Double-blind Period

    Time frame: From Baseline to Week 48

    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.

  8. Summary of Adverse Events During Double-blind Period

    Time frame: From Baseline until Week 48

    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

  9. Incidence and Severity of Adverse Events During Double-blind Period

    Time frame: From Baseline until Week 48

    Adverse events listed according to MedDRA version 20.1 preferred terms and severity grade.

  10. Number of Participants With Adverse Events Leading to Death During Double-blind Period

    Time frame: From Baseline up to Week 48

    Reason of death is coded using MedDRA 20.1

  11. Frequency of Serious Systemic Sclerosis (SSC) Related Complications During Double-blind Period

    Time frame: From Baseline up to Week 48

    Adverse event terms coded using MedDRA 20.1. Includes only those serious events adjudicated as SSC-related complications by an independent external committee.

  12. Incidence of Haematology and Hepatic Laboratory Parameters During Double-blind Period

    Time frame: From Baseline up to Week 48

    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.

  13. Percentage of Participants With Change in Digital Ulcer Count During Double-blind Period

    Time frame: From Baseline to Week 48

    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.

  14. Percentage of Participants With Positive Anti-Tocilizumab Assay Result at Baseline

    Time frame: Baseline

    Incidence of anti-Tocilizumab at baseline

  15. Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline up to Week 48

    Time frame: Double-blind period (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.

  16. Correlation Between Anti-Tocilizumab Antibody Status and Outcome Measures Pertaining to the Efficacy, Safety, and Pharmacokinetics of Tocilizumab

    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)

    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.

  17. Erythrocyte Sedimentation Rate (ESR), Mean, From Baseline to Week 48

    Time frame: From Predose up to Week 48

    Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.

  18. Erythrocyte Sedimentation Rate (ESR), Median, From Baseline to Week 48

    Time frame: From Baseline to Week 48

    Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.

  19. Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 48

    Time frame: From Baseline to Week 48

    Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  20. Serum Interleukin (IL)-6 Level, Median, From Baseline to Week 48

    Time frame: From Baseline to Week 48

    Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  21. Serum Interleukin (IL)-6 Level, Mean Change From Baseline to Week 48

    Time frame: From Baseline to Week 48

    Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  22. Serum Interleukin (IL)-6 Level, Median Change From Baseline to Week 48

    Time frame: From Baseline to Week 48

    Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  23. Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, From Baseline to Week 48

    Time frame: 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.

  24. Serum Soluble Interleukin (IL)-6 Receptor Level, Median, From Baseline to Week 48

    Time frame: 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.

  25. Serum Soluble Interleukin (IL)-6 Receptor Level, Mean Change From Baseline to Week 48

    Time frame: 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.

  26. Serum Soluble Interleukin (IL)-6 Receptor Level, Median Change From Baseline to Week 48

    Time frame: 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.

  27. Serum C-Reactive Protein (CRP) Level, Mean, From Baseline to Week 48

    Time frame: From Baseline up to Week 48

    Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.

  28. Serum C-Reactive Protein (CRP) Level, Median, From Baseline to Week 48

    Time frame: From Baseline up to Week 48

    Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.

  29. Serum Tocilizumab Concentration, Mean, From Baseline to Week 48

    Time frame: From Baseline to Week 48

    Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter

  30. Serum Tocilizumab Concentration, Median, From Baseline to Week 48

    Time frame: From Baseline to Week 48

    Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter

  31. Correlation Between Low Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

    Time frame: 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.

  32. Correlation Between Low Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

    Time frame: 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.

  33. Correlation Between Medium Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

    Time frame: 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.

  34. Correlation Between Medium Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

    Time frame: 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.

  35. Correlation Between High Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

    Time frame: 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.

  36. Correlation Between High Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

    Time frame: 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.

  37. Change in Mean Modified Rodnan Skin Score (mRSS) at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48

    Time frame: 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.

  38. Change in Median Modified Rodnan Skin Score (mRSS), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48

    Time frame: 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.

  39. Change in Mean Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48

    Time frame: 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.

  40. Change in Median Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48

    Time frame: 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.

  41. Summary of Adverse Events Up to Week 96

    Time frame: 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

  42. Incidence and Severity of Adverse Events Up to Week 96

    Time frame: 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.

  43. Number of Participants With Adverse Events Leading to Death Up to Week 96

    Time frame: Up to Week 96

  44. Percentage of Participants With Change in Digital Ulcer Count at Week 96

    Time frame: From Baseline to 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.

  45. Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline From Week 48 to 96

    Time frame: Open-label period 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.

  46. Erythrocyte Sedimentation Rate (ESR) Up to Week 96

    Time frame: Up to Week 96

    Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.

  47. Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 96

    Time frame: Up to Week 96

    Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  48. Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, Up to Week 96

    Time frame: Up to Week 96

    Serum Soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.

  49. Serum C-Reactive Protein (CRP) Level, Mean, Up to Week 96

    Time frame: From Baseline up to Week 96

    Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.

  50. Serum Tocilizumab Concentration, Mean, Up to Week 96

    Time frame: Up to Week 96

    Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter

Sponsors and collaborators

Lead sponsor

Hoffmann-La Roche

Industry

Registry information

Official study title

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy and Safety of Tocilizumab Versus Placebo in Patients With Systemic Sclerosis

Acronym: focuSSced

Important dates

Study start
2015
Primary completion
2018
Study completion
2019
First posted
May 25, 2015
Registry last updated
Mar 9, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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