Ultrasound scores as imaging biomarkers of early response to subcutaneous tocilizumab in association with methotrexate in early rheumatoid arthritis (TOVERA study)

• Register: EUCTR
• Last refreshed on: 23 October 2023
• Main ID: EUCTR2015-001246-28-BE
• Date of registration: 23/07/2015
• Prospective Registration: Yes
• Primary sponsor: Cliniques Universitaires Saint-Luc, Université catholique de Louvain
• Public title: Ultrasound scores as imaging biomarkers of early response to subcutaneous tocilizumab in association with methotrexate in early rheumatoid arthritis (TOVERA study)
• Scientific title: Ultrasound scores as imaging biomarkers of early response to subcutaneous tocilizumab in association with methotrexate in early rheumatoid arthritis (TOVERA study) - TOVERA
• Date of first enrolment: 19/10/2015
• Target sample size: 45
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001246-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: standard of care If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Belgium

Contacts

• Name: Pôle de pathologies rhumatismales
• Affiliation: Cliniques Universitaires Saint-Luc, Université catholique de Louvain

• Name: Pôle de pathologies rhumatismales
• Affiliation: Cliniques Universitaires Saint-Luc, Université catholique de Louvain

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion criteria
1. Diagnosis of RA fulfilling the 2010 EULAR/ACR (European League Against Rheumatism/ American College of Rheumatology classification criteria)
2. Disease duration no longer than 12 months from the time of initial diagnosis
3. Age : 18-70 years
4. Disease activity defined by a disease activity score DAS28-CRP > 3.2 or all must be met: tender joint count (TJC) of =4 and swollen joint count (SJC) =4
5. US SH or PD synovitis scores >1 for at least 2 metacarpophalangeal (MCP) joints (2-5) and US SH or PD synovitis scores =1
6. Naïve to DMARD (methotrexate, leflunomide, sulphasalazine) and biologics (TNF-, IL6-, CD20-, IL1-blockers)

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 35
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion criteria:
Exclusion criteria
1. History of other concomitant autoimmune disease such as lupus or psoriatic arthritis
2. Meeting diagnostic criteria for any other rheumatic disease than RA (e.g. gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, arthropathy or inflammatory bowel disease)
3. Any previous treatment with :
a. Etanercept, infliximab, certolizumab, golimumab, abatacept or adalimumab, anakinra
b. Any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti- CD3, anti-CD19 and anti-CD20
c. Intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
d. Alkylating agents such as chlorambucil, or with total lymphoid irradiation
4. Previous MCP arthroplasty or wrist arthrodesis. Participants who have undergone or are scheduled to undergo joint arthroplasties other than the MCP joints can be recruited in the study provided all other eligibility criteria are met.
5. Current liver disease requiring medication
6. Current symptoms of severe progressive or uncontrolled renal, hematologic, gastro-intestinal, pulmonary, cardiac, neurologic or cerebral disease whether or not related to rheumatoid arthritis, that would jeopardize inclusion in the protocol as judged by the clinician
7. History of malignancy or lymphoproliferative disease, within the last 5 years, with the exception of basal cell or squamous cell carcinoma of the skin or carcinoma in situ of cervix which that has been fully excised/cured with no evidence of recurrence
8. Concomitant diagnosis or 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 GI conditions that might predispose to perforations
9. Evidence of active or latent bacterial, viral, fungal (except for fungal infections of nail beds), mycobacterial or other opportunistic infections at the time of potential enrolment
10. Any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 4 weeks or oral antibiotics within 2 weeks of screening’
11. Herpes zoster or cytomegalovirus infection that resolved less than 2 months before the informed consent was signed
12. Subjects at risk of tuberculosis (TB) are excluded if any of the following is present:
- A history of active TB within the last 3 years, even if treated
- Latent TB that was not successfully treated = 4 weeks
- Current clinical radiographic, or laboratory evidence of active TB
13. Subjects who received live vaccines within 4 weeks of the anticipated first dose of study medication. Live and live attenuated vaccines should not be given concurrently
14. Subjects must agree not to take live attenuated vaccines (including seasonal nasal flu vaccine, varicella vaccine for shingles or chickenpox, MMR or MMRV, oral polio vaccine and vaccines for yellow fever, measles, mumps or rubella) thirty (30) days before the Screening Visit, throughout the duration of the trial and for sixty (60) days following the subject’s last dose of study drug
15. Subjects with positive test results for hepatitis B surface antigen or hepatitis C, or HIV detected with polymerase chain reaction or immunoblot assay
16. Subjects with primary or secondary immunodeficiency
17. History of severe allergic or anaphylactic reactions to human

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Rheumatoid Arthritis
MedDRA version: 18.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Intervention(s)

Trade Name: RoActemra
Product Name: RoActemra
Pharmaceutical Form: Solution for injection/infusion in pre-filled syringe

Primary Outcome(s)

Primary end point(s): Primary end points
Induction phase
Area under the curve of the US parameters (SH, JE, PD, GLOSS) assessing the MCP joints
(2nd to 5th of both hands) and wrists from baseline through 24 weeks

Time to change in US parameters (SH, JE, PD, GLOSS) defined as US improvement (20%, 50%, 70%) of the sum scores of individual joints, from baseline through 24 weeks

US response at week 12 may be predictive of later clinical response at week 24 and week 48



Maintenance phase
4. Area under the curve of the US parameters (SH, JE, PD, GLOSS) assessing MCP joints (2nd to 5th of both hands) from 24 weeks to 54 weeks
5. Area under the curve in PD, SH, JE and GLOSS scores assessing the MCP joints (2nd to 5th of both hands) and wrists from baseline to weeks 54
6. Percentage of patients which have an US improvement (20%, 50%, 70%) in US parameters (SH, JE, PD, GLOSS) of the sum scores of individual joints, at 24 weeks and 48 weeks

Timepoint(s) of evaluation of this end point: To identify the minimum set of joint to be monitored to adequately assess disease activity by comparing the sensitivity to change of different reduced ultrasound joint counts.

Secondary Objective: Main secondary objectives
1.To investigate the mean change from the beginning of maintenance phase to 54 weeks in PD, SH, JE and GLOSS scores for the whole 32-US joint set [time frame: baseline to week 2, 4, 8, 12, 16, 24]
2.To investigate the mean change from the beginning of maintenance phase to 54 weeks in PD, SH, JE, GLOSS scores assessing the MCP (2-5 joints of both hands) [time frame: week 24 to 32, 40, 54]
3.To assess if PD score at 12 weeks is predictive of clinical response at 24 and at 48 weeks
4.To assess the predictive value of PD findings in relation to radiologic outcome at 54 weeks.
5.ACR and EULAR core data set response during the induction and maintenance phase.

Main Objective: Main primary objectives
Induction phase
1.To investigate if an early US response at week 12 may be predictive of later clinical response (week 24 and week 48) and to identify a minimum set of joints to be monitored to adequately assess disease activity
2.To investigate the mean change from baseline PD, SH, JE scores and global scoring system (GLOSS) assessing the MCP (2-5 joints of both hands) and wrists [time frame: baseline to weeks 2, 4, 8, 12, 16, 24]
3.To define the earliest time point at which improvement in PD, SH, JE and GLOSS scores in MCP (2-5 joints of both hands) and wrists can be detected [time frame: weeks 2, 4, 8, 12, 16, 24]
4.To investigate the mean change from baseline to the end of the induction phase in PD, SH, JE and GLOSS scores for the whole 32-US joint set [time frame: baseline to week 2, 4, 8, 12, 16, 24]

Secondary Outcome(s)

Secondary end point(s): Main secondary end points
1. Area under the curve of the US parameters (SH, JE, PD, GLOSS) for the whole 32-US joint set, from 24 weeks to 54 weeks
2. Area under the curve of the US parameters (SH, JE, PD, GLOSS) for the for the whole 32-US joint set, from baseline to 54 weeks
3. ACR and EULAR core data set response during the induction and maintenance phase.

Secondary ID(s)

P1200_14

Source(s) of Monetary Support

Cliniques Universitaires Saint-Luc, Université catholique de Louvain

Ethics review

Status: Approved
Approval date: 19/10/2015
Contact: