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

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ClinicalTrials.gov Identifier: NCT02453256
Recruitment Status : Completed
First Posted : May 25, 2015
Results First Posted : April 3, 2019
Last Update Posted : April 16, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Systemic Sclerosis Drug: Placebo Drug: Tocilizumab Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 212 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : November 20, 2015
Actual Primary Completion Date : January 15, 2018
Actual Study Completion Date : February 4, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Scleroderma
Drug Information available for: Tocilizumab

Arm Intervention/treatment
Placebo Comparator: Double-Blind Placebo
Participants will receive double-blind matching placebo from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Drug: Placebo
Participants will receive matching placebo subcutaneous (SC) injections once weekly for 48 weeks of double-blind treatment.

Drug: Tocilizumab
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.

Experimental: Double-Blind Tocilizumab
Participants will receive double-blind tocilizumab from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Drug: Tocilizumab
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 Outcome Measures :
  1. Change in Modified Rodnan Skin Score (mRSS) [ 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 Outcome Measures :
  1. Percentage of Participants With Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS [ 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) [ 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) [ 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 [ 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 [ 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 [ 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 [ 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 [ 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 [ Time Frame: From Baseline until Week 48 ]
    Adverse events listed according to MedDRA version 20.1 preferred terms and severity grade.

  10. Frequency of Deaths [ 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 [ 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 [ 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. Change in Digital Ulcer Count [ 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 [ Time Frame: 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 [ 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 [ 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 [ 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 [ 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 [ 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 [ 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 Level, Mean [ Time Frame: From Baseline to Week 48 ]
    Serum Soluble Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  24. Serum Soluble Interleukin (IL)-6 Level, Median [ Time Frame: From Baseline to Week 48 ]
    Serum Soluble Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  25. Serum Soluble Interleukin (IL)-6 Level, Mean Change From Baseline [ Time Frame: From Baseline to Week 48 ]
    Serum Soluble Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  26. Serum Soluble Interleukin (IL)-6 Level, Median Change From Baseline [ Time Frame: From Baseline to Week 48 ]
    Serum Soluble Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.

  27. Serum C-Reactive Protein (CRP) Level, Mean [ 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 [ 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 [ Time Frame: From Baseline to Week 48 ]
    Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter

  30. Serum Tocilizumab Concentration, Median [ 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) [ 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) [ 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) [ 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) [ 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) [ 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) [ 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 [ 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 [ 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 [ 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 [ 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02453256


  Show 106 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Statistical Analysis Plan  [PDF] January 23, 2018
Study Protocol  [PDF] May 5, 2017


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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02453256     History of Changes
Other Study ID Numbers: WA29767
2015-000424-28 ( EudraCT Number )
First Posted: May 25, 2015    Key Record Dates
Results First Posted: April 3, 2019
Last Update Posted: April 16, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Scleroderma, Systemic
Scleroderma, Diffuse
Sclerosis
Pathologic Processes
Connective Tissue Diseases
Skin Diseases