Study to Compare the Efficacy of Tocilizumab With or Without Glucocorticoid Discontinuation in Rheumatoid Arthritis Participants

Rheumatoid Arthritis Clinical Trial

Official title:

Prospective, Multicentre, Placebo-controlled, Double-blind Interventional Study to Compare the Efficacy of Maintenance Treatment With Tocilizumab With or Without Glucocorticoid Discontinuation in Rheumatoid Arthritis Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02573012
• Other study ID #: MA29585
• Secondary ID: 2014-004673-16
• Status: Completed
• Phase: Phase 4
• Start date: March 29, 2016
• Est. completion date: February 9, 2018

Study information

• Verified date: October 2019
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This Phase IIIb/IV, two-arm, randomized, double-blind, placebo-controlled, parallel-group, international, multicenter trial compares the change in disease activity (as assessed by Disease Activity Score in 28 joints [DAS28] erythrocyte sedimentation rate [ESR]) from randomization to Week 24 post-randomization, in participants with stable low disease activity [LDA] (DAS28 ESR score less than or equal to [<=] 3.2) who receive tocilizumab, and have been randomized to either continue or taper prednisone in a double-blinded fashion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 314
• Est. completion date: February 9, 2018
• Est. primary completion date: February 9, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Tocilizumab-experienced participants:

• Comply with the requirements of the study protocol (including treatment on an outpatient basis)

• Rheumatoid arthritis (RA) of greater than or equal to (>=) 6 months duration diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria or 2010 ACR / European League Against Rheumatism (EULAR) criteria

• Have received tocilizumab either subcutaneous (162 milligram [mg] once in a week) or intravenously (8 milligram per kilogram [mg/kg] once every 4 weeks) for the treatment of RA for at least 24 weeks prior to randomization

• Have received 5 - 15 milligrams per day [mg/day] of glucocorticoids (prednisone or equivalent) for the treatment of RA for at least 20 weeks prior to screening

• Currently receiving 5 mg/day of prednisone

• Have attained and maintained LDA (DAS28 ESR score <=3.2) or remission (DAS28 ESR score less than [<] 2.6) for at least 4 weeks prior to randomization

Tocilizumab-naïve participants:

• Comply with the requirements of the study protocol (including treatment on an outpatient basis)

• RA of >=6 months duration diagnosed according to the revised 1987 ACR criteria or 2010 ACR / EULAR criteria

• Have active RA (defined as DAS28 ESR score greater than [>] 3.2)

• Are considered by the investigator as inadequate responders to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or biologic disease-modifying anti-rheumatic drugs (bDMARDs)

• Are receiving 5 - 15 mg/day prednisone (or equivalent) for the treatment of RA

Exclusion Criteria:

General

• Major surgery (including joint surgery) within 8 weeks prior to screening, or planned major surgery during the study and up to 6 months after randomization

• Pregnant women or nursing (breastfeeding) mothers

• In females of childbearing potential, a positive serum pregnancy test at screening

• Females of childbearing potential unwilling or unable to use a reliable means of contraception (for example, physical barrier [participant or partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device) during study treatment and for a minimum of 3 months after the last dose of tocilizumab

• Body weight of >=150 kilogram (kg)

• Lack of peripheral venous access

Disease-related

• RA of functional Class 4, as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis

• Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to RA (for example, vasculitis, pulmonary fibrosis, or Felty syndrome). Secondary Sjögren syndrome with RA may be allowed per the discretion of the investigator

• Diagnosed with juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16 years

• Prior or current inflammatory joint disease other than RA (for example, gout, Lyme disease, sero-negative spondyloarthropathy, including reactive arthritis, psoriatic arthritis, arthropathy of inflammatory bowel disease), or prior or current joint infections

• Previous history of primary or secondary adrenal insufficiency

Previous or Concomitant Prohibited Therapy

• Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening

• Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies (for example, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD20)

• Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of screening

• Intraarticular (IA) or parenteral glucocorticoids for the treatment of RA within 4 weeks prior to screening

• Previous treatment with glucocorticoids for conditions other than RA, at any dose and in any formulation used continuously for >1 week, during the last 1 year prior to screening. Topical glucocorticoid creams or ointments for the treatment of skin conditions (for example eczema) are allowed

• Immunization with a live/attenuated vaccine within 30 days prior to screening. Participants must agree not to take live attenuated vaccines (including seasonal nasal flu vaccine, varicella vaccine for shingles or chickenpox, vaccines for measles, mumps or rubella without or with varicella [MMR or MMRV], oral polio vaccine and vaccines for yellow fever), within 30 days before the Screening Visit, throughout the duration of the trial and for 60 days following the last dose of study drug

• Any previous treatment with alkylating agents such as chlorambucil or with total lymphoid irradiation

Laboratory Exclusion Criteria

• Inadequate haematological, renal and liver function

• Positive hepatitis B surface antigen or hepatitis C antibody Previous or Concomitant Conditions

• History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies

• Evidence of current serious uncontrolled cardiovascular (including uncontrolled hyperlipidemia), nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or gastrointestinal (GI) disease

• Current liver disease as determined by the investigator

• History of diverticulitis, peptic ulcer disease, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower gastrointestinal conditions that might predispose to perforations

• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other opportunistic infections (including, but not limited to, tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, Epstein-Barr virus, cytomegalovirus and herpes zoster, but excluding fungal infections of nail beds)

• Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation

• Any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening

• Active TB requiring treatment within the previous 3 years (participants previously treated for TB with no recurrence within 3 years are permitted). All Track tocilizumab-naïve participants must be screened for latent TB and if positive, should be treated following local practice guidelines prior to initiating tocilizumab

• History of or currently active, primary or secondary immunodeficiency

• Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including haematological malignancies and solid tumours, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that was excised and cured), or breast cancer diagnosed within the previous 20 years

• History of alcohol, drug or chemical abuse within 1 year prior to screening

• Pre-existing central nervous system (CNS) demyelination or seizure disorders

• Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Placebo matched to prednisone
Participants will receive placebo matched to prednisone orally for 24 weeks.
• Prednisone
Participants will receive prednisone either at a constant dose of 5 mg/day, or 5 mg/day with 1 mg decrements every 4 weeks orally for 24 weeks.

Biological:
• Tocilizumab
Participants will receive tocilizumab at a dose of 162 mg once a week subcutaneously for 24 weeks.

Locations

Country	Name	City	State
France	Hopital Pellegrin; Rhumatologie	Bordeaux
France	Hopital de La Source	Orleans
France	Hopital Cochin; Rhumatologie B	Paris
France	Hopital Hautepierre; Rhumatologie	Strasbourg
France	Hopital Purpan; Rhumatologie	Toulouse
Germany	Praxis Dr. med. Reiner Kurthen	Aachen
Germany	Asklepios Kllinikum Bad Abbach; Klinik für Rheumatologie und Klinische Immunologie	Bad Abbach
Germany	Rheumatologische Gemeinschaftspraxis Grafschaft, Dr. med. Dorothea Pick, Dr. med. Christopher Amberg	Bad Neuenahr-Ahrweiler
Germany	Charité Campus Mitte, Med.Klinik, Rheumatologie und Klinische Immunologie	Berlin
Germany	SchlossPark-Klinik Berlin; Int. Med. II, Rheum. Osteo	Berlin
Germany	Rheumatologisches MVZ Dresden GmbH, Dres. Holger Schwenke, Reiner Schwenke, Annekatrin Georgi	Dresden
Germany	MVZ Ambulantes Rheumazentrum	Erfurt
Germany	Dres. Florian Schuch, Ruediger de la Camp, Martin Hammerschmidt u.w.	Erlangen
Germany	Praxis Dr.med. Maria Höhle	Hamburg
Germany	Universitätsklinikum Hamburg-Eppendorf Zentrum f.Innere Medizin Med.Klinik III	Hamburg
Germany	Rheumapraxis PD Dr.med. Bernhard Heilig	Heidelberg
Germany	Klinik der Uni zu Köln; Klinik für Innere Medizin	Köln
Germany	Rheumatologische Facharztpraxis Maren Sieburg	Magdeburg
Germany	SMO.MD GmbH, Zentrum für klinische Studien	Magdeburg
Germany	Praxiszentrum St. Bonifatius	Muenchen
Germany	Klinikum der Universitat Munchen; Bereich Pettenkoferstr; Rheumaeinheit der medizinischen Klinik IV	München
Germany	Rheumapraxis an der Hase	Osnabrück
Germany	Rheumazentrum Ratingen - Studienambulanz	Ratingen
Germany	Rheumatologische Schwerpunktpraxis am Feuersee	Stuttgart
Germany	Universitätsklinikum Würzburg; Medizinische Klinik und Poliklinik II; Rheumatologie/Immunologie	Würzburg
Italy	Ospedale Careggi Villa Monnatessa ; Sezione Di Reumatologia	Firenze	Toscana
Italy	Irccs Policlinico San Matteo; Reumatologia Adulti	Pavia	Lombardia
Italy	Arcispedale Santa Maria Nuova; Reumatologia	Reggio Emilia	Emilia-Romagna
Russian Federation	FSBI Scientific Research Institute of Clinical and Experimental Lymphology of SB of RAMS	Novosibirsk
Russian Federation	Perm Regional Clinical Hospital	Perm
Russian Federation	SBEI of HPE "Northwestern State Medical University n.a. I.I.Mechnikov" of MoH of RF	Saint-Petersburg
Russian Federation	Republican clinical hospital named after G.G. Kuvatov	UFA
Russian Federation	City Clinical Hospital # 2	Vladivostok
Serbia	Institute of Rheumatology	Belgrade
Serbia	Military Medical Academy; Clinic of Rheumatology	Belgrade
Serbia	Institute of Rheumatology and Cardiovascular Diseases; Rheumatology	Niska Banja
Serbia	Clinical Center of Vojvodina	Novi Sad
Serbia	Special hospital for rheumatic diseases Novi Sad	Novi Sad
Tunisia	Hopital Farhat Hached; Service Rhumatologie	Sousse

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

France,  Germany,  Italy,  Russian Federation,  Serbia,  Tunisia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Disease Activity Score in 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24 Post-randomization	The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint count, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × v(TJC28)) + (0.28 × v(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100-millimeter (mm) visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A positive change in score indicates worsening, and a negative change indicates improvement.	Baseline to Week 24
Secondary	Treatment Success	Treatment success was defined as the percentage of participants with stable low disease activity (LDA) (DAS28-ESR score = 3.2) at Week 24 post-randomization, who did not suffer a flare due to RA and who showed no confirmed adrenal insufficiency that required replacement therapy. DAS28 has the following standardized cut-offs for disease activity and remission: DAS28 > 5.1 = high disease activity; DAS28 between 3.2 and 5.1 = moderate disease activity; DAS28 = 3.2 = low disease activity; DAS28 = 2.6 = remission.	Week 24
Secondary	Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24	Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index is calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter (cm) visual analog scale (VAS) + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 100 mm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores range from 0 to 76, with higher scores indicating increased disease activity. A positive change in score indicates worsening, and a negative change indicates improvement.	Baseline and Week 24
Secondary	Percentage of Participants With >=1 Flare	Percentage of participants with >=1 flare	24 weeks
Secondary	Time to First RA Flare	The mean time of onset for the first RA flare since randomization.	Randomization to 24 weeks
Secondary	Percentage of Visits With RA Flares		Randomization to 24 weeks
Secondary	Percentage of Participants With >=1 Administration of Flare Rescue Medication	The proportion of participants with at least one administration of RA flare rescue medication.	Randomization to 24 weeks
Secondary	Time to First Administration of Flare Rescue Medication	Time of onset of first administration of RA flare rescue medication since randomization date	Randomization to 24 weeks
Secondary	Number of Administrations of Flare Rescue Medication	Proportion of participants who received courses of RA flare rescue medication by number of courses received.	Randomization to 24 weeks
Secondary	Cumulative Prednisone Exposure (Dose)	In Post-randomization prednisone arm, Cumulative dose = (number of capsules taken during week 1 to 4 * 1 mg) + (3/4 * number of capsules taken during week 5 to 8 * 1 mg) + (1/2 * number of capsules taken during week 9 to 12 * 1 mg) + (1/4 * number of capsules taken during week 13 to 16 * 1 mg). In continued arm, cumulative dose = (1/4 * number of capsule taken * 5 mg).; Cumulative prednisone dose is defined as cumulative blinded prednisone + cumulative flare rescue prednisone.	Randomization to 24 weeks
Secondary	Percentage of Participants Who Maintain LDA (DAS28 ESR Score <=3.2) or Remission (DAS28 ESR Score <2.6) and the Percentage of Participants Who Maintain the Baseline Disease Activity Level	The proportion of participants who maintained LDA and the proportion of participants who maintained the baseline disease activity level at Week 24.; LDA was defined as DAS28 ESR score <= 3.2. Remission was defined as DAS28 ESR score <= 2.6. Participants who maintained the baseline activity was defined as DAS28-ESR at Week 24 <= DAS28-ESR at baseline.	Randomization to Week 24
Secondary	Percentage of Participants Who Permanently Discontinue Study Treatment Due to Insufficient Flare Control	Percentage of participants who permanently discontinue study treatment due to insufficient flare control	24 weeks
Secondary	Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Swollen 66 Joint Counts	Count of swollen joints based upon 66 assessed joints.	Baseline to Week 24
Secondary	Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Tender 68 Joint Counts	Count of tender joints based on 68 assessed joints.	Baseline to Week 24
Secondary	Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Patient's Assessment of Pain	The ACR patient's assessment of pain is scored on a visual analog scale (VAS) from 0 (no pain) to 100 mm (unbearable pain). A positive change in score indicates worsening, and a negative change indicates improvement.	Baseline to Week 24
Secondary	Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Patient's Global Assessment of Disease Activity	The ACR patient's global assessment of disease activity is scored on a visual analog scale (VAS) from 0 (symptom-free and no arthritis symptoms) to 100 mm (maximum arthritis disease activity). A positive change in score indicates worsening, and a negative change indicates improvement.	Baseline to Week 24
Secondary	Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Physician's Global Assessment of Disease Activity	The ACR physician's global assessment of disease activity is scored on a visual analog scale (VAS) from 0 (symptom-free and no arthritis symptoms) to 100 mm (maximum arthritis disease activity). A positive change in score indicates worsening, and a negative change indicates improvement.	Baseline to Week 24
Secondary	Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Health Assessment Questionnaire-Disability Index (HAQ-DI)	A measure of self-perceived disability containing 20 questions in eight categories and including additional section about aid from other people and devices needed to correct the disabilities. Scores range from 0 to 3, with higher scores indicating worse disability.	Baseline to Week 24
Secondary	Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: High Sensitivity C-Reactive Protein (hsCRP)	Change from baseline in the acute phase reactant hsCRP	Baseline to Week 24
Secondary	Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Erythrocyte Sedimentation Rate (ESR)	Change from baseline in the acute phase reactant ESR	Baseline to Week 24
Secondary	Changes From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) Final Score	The RAID is a participant-completed questionnaire specific for RA consisting of a 0-10 rating for pain, functional disability, fatigue, sleep, physical well-being, emotional well-being and coping. Scores are weighted to produce a final numerical result. A positive change in score indicates worsening, and a negative change indicates improvement.	Baseline and Week 24
Secondary	Changes From Baseline in Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) Score	The WPAI:SHP is a 6-item questionnaire to measure performance impairment of work and regular daily activity and yields 4 types of scores: work time missed (absenteeism), impairment while working (presenteeism or reduced on-the-job effectiveness), overall work impairment (WI) (work productivity loss or absenteeism plus presenteeism) and activity impairment (daily activity impairment). Total score and each score range from 0 (not affected/no impairment) to 100 (completely affected/impaired). Higher scores indicate greater impairment and less productivity. A positive change in score indicates impairment, and a negative change indicates improvement.	Baseline and Week 24
Secondary	Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 24	The SDAI is the numerical sum of 5 outcome parameters: tender and swollen joint count based on a 28-joint assessment, patient and physician global assessment of disease activity according to 100-mm visual analog scale (VAS) and level of C-reactive protein in milligrams per deciliter (mg/dL, normal <1 mg/dl). The total SDAI score range is 0-86, where higher scores indicate increased disease activity. A positive change in score indicates worsening, and a negative change indicates improvement.	Randomization to Week 24