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)

Rheumatoid Arthritis Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02046616
• Other study ID #: ML28691
• Secondary ID: 2013-002007-34
• Status: Completed
• Phase: Phase 3
• First received: January 24, 2014
• Last updated: April 11, 2018
• Start date: May 28, 2014
• Est. completion date: September 13, 2016

Study information

• Verified date: April 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 133
• Est. completion date: September 13, 2016
• Est. primary completion date: September 13, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Tocilizumab
Tocilizumab 162 mg will be administered subcutaneously QW.
• 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.
• 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.

Locations

Country	Name	City	State
Denmark	Aalborg Universitetshospital Nord, Reumatologisk Afdeling	Alborg
Denmark	Glostrup Hospital, Reumatologisk Afdeling, Ambulatoriet	Glostrup
Denmark	Gentofte Hospital, Medicinsk Afd. C, Klinik for Gigt- og Rygsygdomme	Hellerup
Denmark	Holbæk Sygehus, Medicinsk Afd., Reumatologisk Amb.15-2	Holbæk
Denmark	Sjællands Universitetshospital, Køge; Reumatologisk Afdeling	Køge
Denmark	Odense Universitetshospital, Reumatologisk Afdeling C, Ambulatoriet	Odense
Denmark	Svendborg Sygehus, Reumatologisk Ambulatorium	Svendborg
Finland	Helsinki University Central Hospital; Rheumatology Clinic	Helsinki
Finland	Kiljavan Lääketutkimus Oy	Hyvinkää
Finland	Central Hospital of Pohjois-Karjala; Outpatient Clinic of Rheumatology	Joensuu
Finland	Keski-Suomen Keskussairaala; Sisätautien Klinikka	Jyväskylä
Finland	Lappeenranta Central Hospital; Outpatient Clinic of Internal Medicine	Lappeenranta
Finland	Oulu University Hospital; Rheumatology	Oulu
Norway	Ålesund Sykehus; Revmatologisk Avdeling	Ålesund
Norway	Haukeland Universitetssykehus; Revmatologisk Avdeling	Bergen
Norway	Drammen sykehus Vestre Viken HF, Revmatologisk avd.	Drammen
Norway	Diakonhjemmet; Reumatolgisk Avdeling	Oslo
Norway	St. Olavs Hospital; Revmatologisk avdeling	Trondheim
Sweden	Länssjukhuset Ryhov; Ortoped- och Reumatolog kliniken	Jönköping
Sweden	Uni Hospital Linkoeping; Dept. of Rheumatology	Linkoeping
Sweden	Skånes Universitetssjukhus Lund; Reumatologkliniken	Lund
Sweden	Skånes Universitetssjukhus Malmö; Reumatologkliniken	Malmo
Sweden	Örebro Uni Hospital; Rheumatology	Oerebro
Sweden	Simrishamns Sjukhus	Simrishamn
Sweden	Karolinska Sjukhuset; Reumatologkliniken D2-1	Stockholm
Sweden	Akademiska sjukhuset, Reumatologkliniken	Uppsala
Sweden	Västmanlands sjukhus Västerås, Reumatologkliniken	Västerås

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Denmark,  Finland,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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	Weeks 2, 4, 8, 12, 16, 20, 24
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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