The purpose of this study is to determine if obinutuzumab is effective in systemic sclerosis
Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue-disease characterized by fibrosis, inflammation, and vasculopathy. SSc is responsible for skin fibrosis that can either be limited or diffuse. The latter phenotype of the disease is commonly associated with visceral involvement and therefore similar to graft versus host disease (GvHD) reaction. It can be life threatening in case of pulmonary or cardiovascular involvement. Nonetheless SSc remains a severe disease responsible for important disability and a poor quality of life. B cell depletion and anti CD20 antibody (rituximab) have proven safety and efficacy in treating diffuse SSc. Obinutuzumab is a new generation anti-CD20 antibody for which efficacy and safety should be evaluated in SSc. The OBINUSS trial was thus designed to evaluate obinutuzumab safety and efficacy in SSc.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
120
1000mg of i.v obinutuzumab at D1, D15 and D180
1000mg of i.v placebo at D1, D15 and D180
Hôpital Cochin
Paris, Île-de-France Region, France
the percentage of patients achieving a 20% CRISS improvement from baseline in at least 3 of the 5-core set second step leasures if the Revised CRISS at 360 days.
Time frame: 360 days
Mortality up to 360 days
Time frame: 360 days
Occurrence of Adverse Events up to 360 days
Time frame: At 90, 180, 270 and 360 days
Occurrence of Severe Adverse Events up to 360 days
Time frame: At 90, 180, 270 and 360 days
Occurrence of AE of specific interest previously mentioned
The number of adverse events, expressed according to the Common Terminology Criteria for Adverse Events (CTCAE): CTCAE toxicity grading system per patient-year at days 180 and 360 for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hospitalization resulting either from the disease or from a complication due to the study treatment. \- Gammaglobulin and CD19 levels at 90, 180, 270 and 360 days
Time frame: At 90, 180, 270 and 360 days
Proportion of patients who achieved CRISS20 of the revised CRISS
Time frame: At days 180 and 270
Proportions of patients who achieved 30%, 40%, 50% ,60%, 70%, 80%, 90% and 100% improvement from baseline in at least 3 of the 5 core set measures of the revised CRISS
Time frame: At days 180, 270 and 360
Change in the Combined Response Index in Diffuse Systemic Sclerosis (CRISS) score.These scales range from 0 (minimum) to 1(maximum) points. Higher score mean better outcome
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Time frame: At days 180, 270 and 360
Change in Physicians visual analogue scales over 18 months
These scales range from 0 (minimum) to ten (maximum) points and will be performed at day 0, at 6, 12, and 18 months. Higher score mean better outcome. Higher score mean worse outcome
Time frame: At 18 months
Change in patients visual analogue scales over 18 month
These scales range from 0 (minimum) to ten (maximum) points and will be performed at day 0, at 6, 12, and 18 months. Higher score mean better outcome
Time frame: At 18 months
Change in modified Rodnan skin score
Range from 0 (minimum) to 100% (maximum). Higher score mean better outcome
Time frame: At 90, 180, 270 and 360 days
Proportion of patients with an improved modified Rodnan skin score.
Time frame: At 90, 180, 270, 360 days
Absolute change from baseline in Forced Vital Capacity FVC
to look for a difference in Pulmonary function tests between patients treated with obinutuzumab and placebo, changes in forced vital capacity FVC and DLCO (% predicted and ml)
Time frame: At days 180, 270, and days 360
Absolute change from baseline in DLCO
to look for a difference in Pulmonary function tests between patients treated with obinutuzumab and placebo, changes in forced vital capacity FVC and DLCO (% predicted and ml)
Time frame: At day 180, 270 and day 360
Proportion of patients with an active disease according to the EUSTAR SSc activity score.
Time frame: At 90, 180, 270 and 360 days.
Time to treatment failure.
Defined as the time to one of the following events (whichever occurs first) occurring over the 48 weeks: death, absolute decline in %-predicted FVC \>/= 10 relative to baseline, \>/= 25% increase in mRSS and an increase in mRSS of 5 points, initiation or dose change of MTX/MMF due to clinically significant deterioration.
Time frame: Over the 48 weeks
Change in skin transcriptome.
According to Khanna et al. Arthritis Rheumatol. 2019 Dec 10;72(1):125-136
Time frame: At 360 days
Analysis of the mouth opening trajectory
Time frame: At days 0, 90, 180, 270 and 360
SF-36 scale
range from 0 (minimum) to 100 (maximum) points and will be performed at day 0, at 6, 12, and 18 months. Higher score mean better outcome
Time frame: At day 0, 90, 180, 270 and day 360
EQ5D5L scale
comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a five-point scale, from 1 (no problems) to 5 (extreme problems), with higher scores reflecting worse health status. The overall EQ-5D-5L utility index is derived using the French country-specific value set, with higher utility scores reflecting better health status
Time frame: At day 0, 90, 180, 270 and day 360
HAQ-DI scale
range from 0 (minimum) to 3 (maximum) points. Higher score mean worse outcome
Time frame: At day 0, 90, 180, 270 and day 360.
SHAQ scale
range from 0 (minimum) to 3 (maximum) points. Higher score mean worse outcome
Time frame: At day 0, 90, 180, 270 and day 360.
Saint Georges Respiratory Hospital Questionnaire (SGRH)
range from 0 (minimum) to one hundred (maximum) points. Higher score mean worse outcome
Time frame: At day 0, 90, 180, 270 and day 360
King Brief's Interstitial Lung Disease questionnaire (KBILD)
range from 0 (minimum) to 100 (maximum) points. Higher score mean better outcome
Time frame: At day 0, 90, 180, 270 and day 360
Scleroderma skin patients reported outcome (SSPRO)
range from 0 (minimum) to 108 (maximum) points. Higher score mean worse outcome
Time frame: At day 0, 90, 180, 270 and day 360
PRO self-administered questionnaire (ScleroID)
range from 0 (minimum) to 10 (maximum) points. Higher score mean worse outcome
Time frame: At day 0, 90, 180, 270 and day 360