A Study of Subcutaneous (SC) Tocilizumab (RoActemra/Actemra) in Participants With Active Rheumatoid Arthritis (RA) and Inadequate Response to Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Tocilizumab SC in Patients With Active Rheumatoid Arthritis and Inadequate Response to DMARDs. A Single-Arm, Open-Label Study to Evaluate Safety, Tolerability and Efficacy. In a Subgroup of Patients Inflammation Will Be Measured by Ultrasound.

This Phase IIIb, open-label, single-arm study will evaluate the safety, efficacy, and tolerability of SC tocilizumab (RoActemra/Actemra) in monotherapy or in combination with methotrexate or other non-biologic DMARDs in participants with active RA who are naive to tocilizumab. Participants will receive tocilizumab 162 milligrams (mg) subcutaneously weekly (QW) for 24 weeks.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Tocilizumab; Drug: Methotrexate; Drug: Non-Biologic DMARDs

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Alborg, Denmark, 9000
    • Aalborg Universitetshospital Nord, Reumatologisk Afdeling
  • Glostrup, Denmark, 2600
    • Glostrup Hospital, Reumatologisk Afdeling, Ambulatoriet
  • Hellerup, Denmark, 2900
    • Gentofte Hospital, Medicinsk Afd. C, Klinik for Gigt- og Rygsygdomme
  • Holbæk, Denmark, 4300
    • Holbæk Sygehus, Medicinsk Afd., Reumatologisk Amb.15-2
  • Køge, Denmark, 4600
    • Sjællands Universitetshospital, Køge; Reumatologisk Afdeling
  • Odense, Denmark, 5000
    • Odense Universitetshospital, Reumatologisk Afdeling C, Ambulatoriet
  • Svendborg, Denmark, 5700
    • Svendborg Sygehus, Reumatologisk Ambulatorium
• Finland
  • Helsinki, Finland, 00290
    • Helsinki University Central Hospital; Rheumatology Clinic
  • Hyvinkää, Finland, 05800
    • Kiljavan Lääketutkimus Oy
  • Joensuu, Finland, 80210
    • Central Hospital of Pohjois-Karjala; Outpatient Clinic of Rheumatology
  • Jyväskylä, Finland, 40620
    • Keski-Suomen Keskussairaala; Sisätautien Klinikka
  • Lappeenranta, Finland, 53130
    • Lappeenranta Central Hospital; Outpatient Clinic of Internal Medicine
  • Oulu, Finland, 90220
    • Oulu University Hospital; Rheumatology
• Norway
  • Bergen, Norway, 5053
    • Haukeland Universitetssykehus; Revmatologisk Avdeling
  • Drammen, Norway, 3004
    • Drammen sykehus Vestre Viken HF, Revmatologisk avd.
  • Oslo, Norway, 0370
    • Diakonhjemmet; Reumatolgisk Avdeling
  • Trondheim, Norway, 7030
    • St. Olavs Hospital; Revmatologisk avdeling
  • Ålesund, Norway, 6017
    • Ålesund Sykehus; Revmatologisk Avdeling
• Sweden
  • Jönköping, Sweden, 551 85
    • Länssjukhuset Ryhov; Ortoped- och Reumatolog kliniken
  • Linkoeping, Sweden, 58185
    • Uni Hospital Linkoeping; Dept. of Rheumatology
  • Lund, Sweden, 221 85
    • Skånes Universitetssjukhus Lund; Reumatologkliniken
  • Malmo, Sweden, 205 02
    • Skånes Universitetssjukhus Malmö; Reumatologkliniken
  • Oerebro, Sweden, 70185
    • Örebro Uni Hospital; Rheumatology
  • Simrishamn, Sweden, 272 81
    • Simrishamns Sjukhus
  • Stockholm, Sweden, 171 76
    • Karolinska Sjukhuset; Reumatologkliniken D2-1
  • Uppsala, Sweden, 75185
    • Akademiska sjukhuset, Reumatologkliniken
  • Västerås, Sweden, 72189
    • Västmanlands sjukhus Västerås, Reumatologkliniken

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Active RA according to the revised ACR (1987) criteria or EULAR/ACR (2010) criteria
• Moderate to severe RA with a DAS28-ESR score >3.2 points
• Inadequate response and/or intolerance to MTX or other non-biologic DMARDs and/or where MTX or other non-biologic DMARDs are inappropriate
• Oral corticosteroids (less than or equal to [</=] 10 mg per day prednisolone or equivalent) and nonsteroidal anti-inflammatory drugs (NSAIDs) permitted if on stable dose regimen for greater than or equal to [>/=] 4 weeks prior to baseline
• Permitted non-biologic DMARDs allowed if at stable dose for >/=4 weeks prior to baseline
• Receiving treatment on an outpatient basis, not including tocilizumab
• Agreement to use reliable means of contraception as defined by protocol, among females of childbearing potential and males with female partners of childbearing potential

Exclusion Criteria:

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following baseline
• Rheumatic autoimmune disease other than RA
• Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
• Diagnosis of juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16
• Prior history of or current inflammatory joint disease other than RA
• Exposure to tocilizumab or any other biologic DMARDs at any time prior to baseline
• Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
• Intra-articular or parenteral corticosteroids within 4 weeks prior to baseline
• History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
• Evidence of serious concomitant disease or disorder
• Known active current or history of recurrent infection
• Any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
• Active tuberculosis requiring treatment within the previous 3 years
• Positive for hepatitis B or hepatitis C
• History of or current active primary or secondary immunodeficiency
• Pregnant or lactating women
• Neuropathies or other conditions that might interfere with pain evaluation
• Inadequate hematologic, renal, or liver function

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tocilizumab Alone or Combined with Methotrexate or Other DMARD; All participants will receive tocilizumab as a single fixed dose (monotherapy) or in combination with methotrexate or other non-biologic DMARDs, irrespective of body weight, for 24 weeks.

Drug: Tocilizumab; Tocilizumab 162 mg will be administered subcutaneously QW.; Other Names: RoActemra, Actemra; Drug: Methotrexate; Methotrexate dosing is not specified by the protocol and will be given as per standard practice. Participants must be at a stable dose that was initiated at least 4 weeks prior to baseline.; Drug: Non-Biologic DMARDs; Participants will receive non-biologic DMARDs (same non-biologic DMARD that participant was receiving at time of study entry). Dosing is not specified by the protocol and will be given as per standard practice. Participants must be at a stable dose that was initiated at least 4 weeks prior to baseline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 12	CDAI was derived as the sum of the following: tender joint count (TJC), swollen joint count (SJC), participant global assessment (PGA) of disease activity, and physician assessment of disease activity. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 millimeters (mm) and rounded to the nearest centimeter (cm) on a visual analog scale (VAS), where higher scores indicate greater perceived disease activity. The total CDAI score range was 0-76, where higher scores indicate increased disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Disease Activity Score 28 (DAS28)-Erythrocyte Sedimentation Rate (ESR) Score	DAS28-ESR was based on TJC, SJC, PGA of disease activity, and laboratory-derived ESR. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA of disease activity was scored 0-100 mm on a VAS, where higher scores indicate greater perceived disease activity. The total DAS28-ESR score was transformed to a single score range of 0-10, where higher scores indicate increased disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24
Percentage of Participants With American College of Rheumatology (ACR) Response	ACR response was assessed on the basis of percent improvement (20% for ACR20, 50% for ACR50, 70% for ACR70) in both TJC and SJC as well as at least three of the following: physician assessment of disease activity, PGA of disease activity, PGA of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), and either ESR or C-reactive protein level. TJC and SJC were taken as the number of tender and swollen joints, out of 68 and 66 assessed joints, respectively. PGA and physician assessments were scored 0-100 mm on a VAS, where higher scores indicate greater perceived disease activity or pain. HAQ-DI was scored using participant responses to 20 questions assessing activities of daily living (ADLs), with total score scale of 0-3, where higher scores indicate increased functional disability. The percentage of participants meeting criteria for each level of ACR response was reported.	Weeks 2, 4, 8, 12, 16, 20, 24
Percentage of Participants With European League Against Rheumatism (EULAR) Response	EULAR response was assessed by change from baseline and absolute DAS28-ESR score. EULAR response classification was as follows: Good (change >1.2 with absolute score </=3.2), Moderate (change >1.2 with absolute score >3.2 or change >0.6 with absolute score </=5.1), None (change </=0.6 or absolute score >5.1). DAS28-ESR was based on TJC, SJC, and PGA of disease activity, and laboratory-derived ESR. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA of disease activity was scored 0-100 mm on a VAS, where higher scores indicate greater perceived disease activity. The total DAS28-ESR score was transformed to a single score range of 0-10, where higher scores indicate increased disease activity. The percentage of participants meeting criteria for each level of EULAR response was reported.	Weeks 2, 4, 8, 12, 16, 20, 24
Change From Baseline in CDAI at Weeks 2, 4, 8, 16, 20, and 24	CDAI was derived as the sum of the following: TJC, SJC, PGA of disease activity, and physician assessment of disease activity. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 mm and rounded to the nearest cm on a VAS, where higher scores indicate greater perceived disease activity. The total CDAI score range was 0-76, where higher scores indicate increased disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity.	Baseline and Weeks 2, 4, 8, 16, 20, 24
Change From Baseline in Simplified Disease Activity Index (SDAI)	SDAI was derived as the sum of the following: TJC, SJC, PGA of disease activity, physician assessment of disease activity, and laboratory-derived C-reactive protein level. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 mm and rounded to the nearest cm on a VAS, where higher scores indicate greater perceived disease activity. The total SDAI score range was 0-86, where higher scores indicate increased disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24
Change From Baseline in TJC	TJC was taken as the number of tender joints out of 28 assessed joints.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24
Change From Baseline in SJC	SJC was taken as the number of swollen joints out of 28 assessed joints.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24
Percentage of Participants With At Least One Adverse Event Leading to Dosage Modification	The percentage of participants with at least one adverse event leading to dose/frequency reduction or temporary dose hold was reported.	Baseline up to Week 24
Number of Participants With Neutralizing Anti-Tocilizumab Antibodies	Participants were evaluated for the presence of anti-tocilizumab antibodies. Confirmatory assays were performed in the case of a positive screen assay result.	Baseline to FU Week 8 (up to 32 weeks overall)
Tocilizumab Concentration	Tocilizumab concentration was determined, averaged among all participants, and expressed in micrograms per milliliter (mcg/mL).	Predose (30 minutes) at baseline; Weeks 12, 24; and FU Week 8 (up to 32 weeks overall)
Soluble Interleukin-6 Receptor (sIL-6R) Concentration	sIL-6R concentration was determined, averaged among all participants, and expressed in nanograms per milliliter (ng/mL).	Predose (30 minutes) at baseline; Weeks 12, 24; and FU Week 8 (up to 32 weeks overall)
Change From Baseline in Patient Global Assessment of Disease Activity According to VAS	PGA of disease activity was scored 0-100 mm on a VAS, where higher scores indicate greater perceived disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24
Change From Baseline in Patient Global Assessment of RA-Related Pain According to VAS	PGA of RA-related pain was scored 0-100 mm on a VAS, where higher scores indicate greater perceived pain. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA-related pain.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24
Change From Baseline in HAQ-DI Score	HAQ-DI consisted of 20 questions assessing ADLs in 8 domains (dress/groom, arise, eat, walk, reach, grip, hygiene) with each item rated 0 (no difficulty) to 3 (unable to do). The highest score recorded for any question in a domain determined the score for that domain, unless assistance was required. The total HAQ-DI score was the sum of domain scores divided by the number of domains answered/scored, for a single score range of 0-3, where higher scores indicate increased functional disability. Change from baseline was averaged among all participants. Negative values indicate improvement in ability to perform ADLs.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24
Compliance With Treatment According to Percentage of Injections Administered	Participants were provided with diary cards to record home injections. Compliance with treatment was calculated individually for each participant as the actual number of injections as a percentage of the planned number of injections (up to the point of discontinuation for those who discontinued study treatment prematurely) and then averaged among all participants.	Baseline up to Week 24
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score	FACIT-F consisted of 40 questions/statements assessing chronic illness therapy with special emphasis on fatigue over the past 7 days, with each item rated 0 (not at all) to 4 (very much). During score calculations, negatively-worded item scales (e.g., "I have a lack of energy") were reversed so that higher scores indicated more favorable conditions. The total FACIT-F score was the sum of all item scores and ranged 0-160, and the brief FACIT-F score was the sum of 13 item scores and ranged 0-52, where higher scores indicate greater well-being. Change from baseline was averaged among all participants. Positive values indicate improvement in well-being.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Devenport J, Petho-Schramm A. Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis. Rheumatology (Oxford). 2019 Jun 1;58(6):1056-1064. doi: 10.1093/rheumatology/key393.
• Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Bernasconi C, Petho-Schramm A. Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries. Rheumatology (Oxford). 2018 Mar 1;57(3):499-507. doi: 10.1093/rheumatology/kex443. Erratum In: Rheumatology (Oxford). 2018 Jun 1;57(6):1129.
• Hammer HB, Jensen Hansen IM, Jarvinen P, Leirisalo-Repo M, Ziegelasch M, Agular B, Terslev L. Rheumatoid arthritis patients with predominantly tender joints rarely achieve clinical remission despite being in ultrasound remission. Rheumatol Adv Pract. 2021 May 14;5(2):rkab030. doi: 10.1093/rap/rkab030. eCollection 2021.
• Hammer HB, Hansen I, Jarvinen P, Leirisalo-Repo M, Ziegelasch M, Agular B, Terslev L. Major reduction of ultrasound-detected synovitis during subcutaneous tocilizumab treatment: results from a multicentre 24 week study of patients with rheumatoid arthritis. Scand J Rheumatol. 2021 Jul;50(4):262-270. doi: 10.1080/03009742.2020.1845394. Epub 2021 Jan 19.

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2014
• Primary Completion (Actual): September 13, 2016
• Study Completion (Actual): September 13, 2016

Study Registration Dates

• First Submitted: January 24, 2014
• First Submitted That Met QC Criteria: January 24, 2014
• First Posted (Estimate): January 28, 2014

Study Record Updates

• Last Update Posted (Actual): April 13, 2018
• Last Update Submitted That Met QC Criteria: April 11, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: ML28691; 2013-002007-34 (EudraCT Number)