Clinical trial NCT02453256: A Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis (SSc)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Systemic Sclerosis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-05-25
Enrollment: 212
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Change in Modified Rodnan Skin Score (mRSS) During Double-blind Period
timeFrame: From baseline to week 48
Secondary outcomes:
measure: Percentage of Participants With Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS During Double-blind Period
timeFrame: From Baseline to Week 48
measure: Change From Baseline in Percent Predicted FVC (ppFVC) During Double-blind Period
timeFrame: Baseline to week 48
measure: Change in Forced Vital Capacity (FVC) During Double-blind Period
timeFrame: From Baseline to Week 48
measure: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) Score During Double-blind Period
timeFrame: From Baseline to Week 48
measure: Change in Patient Global Assessment Score During Double-blind Period
timeFrame: From Baseline to Week 48
measure: Change in Physician Global Assessment Score During Double-blind Period
timeFrame: From Baseline to Week 48
measure: Time to Treatment Failure According to mRSS, FVC, or Protocol-Specified Event During Double-blind Period
timeFrame: From Baseline to Week 48
measure: Summary of Adverse Events During Double-blind Period
timeFrame: From Baseline until Week 48
measure: Incidence and Severity of Adverse Events During Double-blind Period
timeFrame: From Baseline until Week 48
measure: Number of Participants With Adverse Events Leading to Death During Double-blind Period
timeFrame: From Baseline up to Week 48
measure: Frequency of Serious Systemic Sclerosis (SSC) Related Complications During Double-blind Period
timeFrame: From Baseline up to Week 48
measure: Incidence of Haematology and Hepatic Laboratory Parameters During Double-blind Period
timeFrame: From Baseline up to Week 48
measure: Percentage of Participants With Change in Digital Ulcer Count During Double-blind Period
timeFrame: From Baseline to Week 48
measure: Percentage of Participants With Positive Anti-Tocilizumab Assay Result at Baseline
timeFrame: Baseline
measure: Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline up to Week 48
timeFrame: Double-blind period (up to Week 48)
measure: Correlation Between Anti-Tocilizumab Antibody Status and Outcome Measures Pertaining to the Efficacy, Safety, and Pharmacokinetics of Tocilizumab
timeFrame: 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)
measure: Erythrocyte Sedimentation Rate (ESR), Mean, From Baseline to Week 48
timeFrame: From Predose up to Week 48
measure: Erythrocyte Sedimentation Rate (ESR), Median, From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Interleukin (IL)-6 Level, Median, From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Interleukin (IL)-6 Level, Mean Change From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Interleukin (IL)-6 Level, Median Change From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Soluble Interleukin (IL)-6 Receptor Level, Median, From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Soluble Interleukin (IL)-6 Receptor Level, Mean Change From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Soluble Interleukin (IL)-6 Receptor Level, Median Change From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum C-Reactive Protein (CRP) Level, Mean, From Baseline to Week 48
timeFrame: From Baseline up to Week 48
measure: Serum C-Reactive Protein (CRP) Level, Median, From Baseline to Week 48
timeFrame: From Baseline up to Week 48
measure: Serum Tocilizumab Concentration, Mean, From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Serum Tocilizumab Concentration, Median, From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Correlation Between Low Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Correlation Between Low Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Correlation Between Medium Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Correlation Between Medium Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Correlation Between High Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Correlation Between High Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Change in Mean Modified Rodnan Skin Score (mRSS) at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Change in Median Modified Rodnan Skin Score (mRSS), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Change in Mean Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Change in Median Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Summary of Adverse Events Up to Week 96
timeFrame: Up to Week 96
measure: Incidence and Severity of Adverse Events Up to Week 96
timeFrame: Up to Week 96
measure: Number of Participants With Adverse Events Leading to Death Up to Week 96
timeFrame: Up to Week 96
measure: Percentage of Participants With Change in Digital Ulcer Count at Week 96
timeFrame: From Baseline to Week 96
measure: Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline From Week 48 to 96
timeFrame: Open-label period from Week 48 to 96
measure: Erythrocyte Sedimentation Rate (ESR) Up to Week 96
timeFrame: Up to Week 96
measure: Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 96
timeFrame: Up to Week 96
measure: Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, Up to Week 96
timeFrame: Up to Week 96
measure: Serum C-Reactive Protein (CRP) Level, Mean, Up to Week 96
timeFrame: From Baseline up to Week 96
measure: Serum Tocilizumab Concentration, Mean, Up to Week 96
timeFrame: Up to Week 96
Other outcomes:
Locations:
city: El Cajon
country: United States
facility: TriWest Research Associates, LLC
state: California
city: Fullerton
country: United States
facility: St. Joseph's Heritage Healthcare
state: California
city: Los Angeles
country: United States
facility: Univ of Calif., Los Angeles; Rheumatology
state: California
city: Los Angeles
country: United States
facility: Arthritis Associates of Southern California
state: California
city: Washington
country: United States
facility: Georgetown Uni. Hosp.; Rheumatology, Immunology and Allergy Dept.
state: District of Columbia
city: Boca Raton
country: United States
facility: Rheumatology Assoc. of S. Florida - Clinical Research Center
state: Florida
city: Ormond Beach
country: United States
facility: Millenium Research
state: Florida
city: Boston
country: United States
facility: Boston Univ Med Center - AC
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: West Michigan Rheumatology, PLLC
state: Michigan
city: Charlotte
country: United States
facility: Joint & Muscle Research Institute
state: North Carolina
city: Oklahoma City
country: United States
facility: Arthritis and Rheumatology; Center of Oklahoma PLLC
state: Oklahoma
city: Philadelphia
country: United States
facility: Thomas Jefferson Uni ; Division of Rheumatology
state: Pennsylvania
city: Wyomissing
country: United States
facility: Clinical Research Center of Reading
state: Pennsylvania
city: Jackson
country: United States
facility: West Tennessee Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Metroplex Clinical Research
state: Texas
city: Buenos Aires
country: Argentina
facility: Organizacion Medica de Investigacion
city: Buenos Aires
country: Argentina
facility: Hospital Britanico; Haematology
city: Rosario, Santa FE
country: Argentina
facility: Sanatorio Parque S.A.
city: Tucuman
country: Argentina
facility: Centro de Investigaciones Reumatologicas Tucuman
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Plovdiv
country: Bulgaria
facility: MHAT Kaspela; Rheumatology
city: Plovdiv
country: Bulgaria
facility: MHAT-Plovdiv AD; Reumatology Department
city: Sofia
country: Bulgaria
facility: MHAT St.Ivan Rilski; Rheumtology Department
city: Sofia
country: Bulgaria
facility: MHAT Sv.Ivan Rilski; Clinic of Rheumatology
city: Vancouver
country: Canada
facility: St. Paul's Hospital University of British Colambia Division of Hematology
state: British Columbia
city: Toronto
country: Canada
facility: Mount Sinai Hospital; Rebecca Macdonald Centre For Arthritis & Autoimmune Disease
state: Ontario
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital Skejby, Hud- og Kønssygdomme
city: København NV
country: Denmark
facility: Bispebjerg Hospital, Dermatologisk afdeling
city: Lille
country: France
facility: Hopital Claude Huriez; Internal Medicine
city: Bad Abbach
country: Germany
facility: Asklepios Kllinikum Bad Abbach; Klinik für Rheumatologie und Klinische Immunologie
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik; Rheumatologie&klin.Immunologie
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden; Technische Universität Dresden; Rheumatologie, Innere Medizin III
city: München
country: Germany
facility: Klinikum der Universitat Munchen; Bereich Pettenkoferstr; Rheumaeinheit der medizinischen Klinik IV
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II
city: Athens
country: Greece
facility: Laiko General Hospital; Dept. of Pathophysiology-Uni of Athens
city: Patras
country: Greece
facility: University Hospital of Patras; Rheumatology
city: Budapest
country: Hungary
facility: National Institute of Rheumatology and Physiology
city: Pécs
country: Hungary
facility: Pécsi Tudományegyetem Klinikai Központ: Immunológiai és Reumatológiai Klinika
city: Napoli
country: Italy
facility: Policlinico Universitario-II Università di Napoli; Reumatologia
state: Campania
city: Roma
country: Italy
facility: Uni ' Cattolica Del Sacro Cuore; Facoltà Di Medicina E Chirurgia A.Gemelli-Clinica Reumatologica
state: Lazio
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico; Unità Operativa Complessa di Allergologia e Immunologia Clinica
state: Lombardia
city: Firenze
country: Italy
facility: Ospedale Careggi Villa Monnatessa ; Sezione Di Reumatologia
state: Toscana
city: Gunma
country: Japan
facility: Gunma University Hospital
city: Hokkaido
country: Japan
facility: Sapporo Medical University Hospital
city: Hokkaido
country: Japan
facility: Hokkaido University Hospital
city: Ishikawa
country: Japan
facility: Kanazawa University Hospital
city: Kanagawa
country: Japan
facility: St. Marianna University School of Medicine Hospital
city: Kitakyushu-shi
country: Japan
facility: Hospital of the University of Occupational and Environmental Health,Japan
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Miyagi
country: Japan
facility: Tohoku University Hospital
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Tokyo
country: Japan
facility: Nippon Medical School Hospital
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
city: Klaipeda
country: Lithuania
facility: Klaipeda University Hospital; Department of Rheumatology
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santariskiu Clinic Public Insti
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Médicas Y de La Nutricion Zubirán
city: Mexico
country: Mexico
facility: Unidad De Enfermedades; Cronico Degenerativas, SC.
city: Miexico City
country: Mexico
facility: Cliditer SA de CV
city: Leiden
country: Netherlands
facility: Academisch Ziekenhuis Leiden; Dept of Rheumatology
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki; nr 2 im. Dr J. Biziela; Klinika Reumatologii i Ukladowych Chorob
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne; Klinika Chorob Wewnetrznych, Chorob Tkanki Łacznej i Geriatrii
city: Katowice
country: Poland
facility: Gornoslaskie Centrum Medyczne
city: Krakow
country: Poland
facility: Szpital Specjalistyczny im Jozefa Dietla; Centrum Reumatologii, Immunologii i Rehabilitacji, I Oddzi
city: Lublin
country: Poland
facility: SPSK NR 4; Reumatologii i Ukladowych Chorob Tkanki
city: Warszawa
country: Poland
facility: Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji im. Prof. Eleonory Reicher
city: Almada
country: Portugal
facility: Hospital Garcia de Orta; Servico de Reumatologia
city: Amadora
country: Portugal
facility: Hospital Prof. Dr. Fernando Fonseca; Medicina IV
city: San Juan
country: Puerto Rico
facility: Puerto Rico Clinical & Translational Research Consortium
city: Bucharest
country: Romania
facility: Cantacuzino Hospital; Department of Internal Medicine and Rheumatology
city: Cluj-napoca
country: Romania
facility: Spitalul Judetean Cluj; Sectia de Reumatologie
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau; Servicio de Medicina Interna/Reumatologia
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron; Servicio de Medicina Interna
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon; Servicio de Reumatología
city: Basel
country: Switzerland
facility: Universitätsspital Basel; Rheumatologische Poliklinik
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich; Klinik für Rheumatologie
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital; Rheumatology Dept.
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Leeds
country: United Kingdom
facility: Chapel Allerton Hospital; Leeds Institution of Rheumatology Medicine
city: Liverpool
country: United Kingdom
facility: Uni Hospital Aintree; Academic Rheumatology Unit
city: London
country: United Kingdom
facility: Royal Free Hospital; Department of Rheumatology
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital; Musculoskeletal Unit
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Khanna D, Lin CJF, Furst DE, Wagner B, Zucchetto M, Raghu G, Martinez FJ, Goldin J, Siegel J, Denton CP. Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis-Interstitial Lung Disease: Open-Label Extension of a Phase 3 Randomized Controlled Trial. Am J Respir Crit Care Med. 2022 Mar 15;205(6):674-684. doi: 10.1164/rccm.202103-0714OC.
citation: Roofeh D, Lin CJF, Goldin J, Kim GH, Furst DE, Denton CP, Huang S, Khanna D; focuSSced Investigators. Tocilizumab Prevents Progression of Early Systemic Sclerosis-Associated Interstitial Lung Disease. Arthritis Rheumatol. 2021 Jul;73(7):1301-1310. doi: 10.1002/art.41668. Epub 2021 May 25.
citation: Gao X, Jia G, Guttman A, DePianto DJ, Morshead KB, Sun KH, Ramamoorthi N, Vander Heiden JA, Modrusan Z, Wolters PJ, Jahreis A, Arron JR, Khanna D, Ramalingam TR. Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis. Cell Rep Med. 2020 Nov 17;1(8):100140. doi: 10.1016/j.xcrm.2020.100140. eCollection 2020 Nov 17.
citation: Khanna D, Lin CJF, Furst DE, Goldin J, Kim G, Kuwana M, Allanore Y, Matucci-Cerinic M, Distler O, Shima Y, van Laar JM, Spotswood H, Wagner B, Siegel J, Jahreis A, Denton CP; focuSSced investigators. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020 Oct;8(10):963-974. doi: 10.1016/S2213-2600(20)30318-0. Epub 2020 Aug 28.