A Study of the Efficacy and Safety of Rituximab in Participants With Systemic Sclerosis

Study Overview
=================
Brief Summary
-----------------
This study evaluates the efficacy and safety of rituximab compared with placebo in SSc patients. This study consists of a 24-week, double-blind, placebo-controlled period followed by a 24-week active drug treatment period.

Official Title
-----------------
Double-Blind, Parallel-group Comparison, Investigators Initiated Phase II Clinical Trial of IDEC-C2B8 (Rituximab) in Patients With Systemic Sclerosis

Conditions
-----------------
Scleroderma, Systemic, Skin Sclerosis, Lung Fibrosis, Autoimmune Diseases, Collagen Diseases

Intervention / Treatment
-----------------
* Drug: Double-Blind Placebo
* Drug: Double-Blind Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Fulfill the diagnostic criteria for systemic sclerosis defined in the 2016 edition of the Clinical Practice Guidelines for Systemic Sclerosis and have an mRTSS of 2 (moderate) or higher for skin sclerosis Aged 20 or older and younger than 80 at the time of consent Have an expected survival of at least 6 months (and expected to allow 6 months of observation) Fulfill the following criteria related to concomitant medications/therapies: Not received corticosteroids equivalent to more than 10 mg/day of prednisolone within 2 weeks before the start of study treatment; and Not received antifibrotic agents (like nintedanib, pirfenidone, tocilizumab), other investigational products, immunosuppressants (cyclophosphamide, mycophenolate mofetil, ciclosporin, tacrolimus, azathioprine, and mizoribine), high-dose intravenous immunoglobulin, or imatinib 4 weeks prior to the start of study treatment. Provided written consent to participate in the study Exclusion Criteria: Present with pulmonary hypertension* associated with systemic sclerosis *: The patient will undergo echocardiography during the pre-treatment observation period to exclude pulmonary hypertension. The patient will be required to undergo examination by an expert (eg, at the Department of Cardiovascular Medicine) if systolic pulmonary artery pressure exceeds 35 mmHg. Have serious complications (eg, renal crisis) associated with systemic sclerosis (excluding interstitial pneumonia**) **: Patients with interstitial pneumonia will be excluded if the criterion 3) below is met. Have only poor respiratory reserve (%VC or %DLco, both calculated using the estimation equation more suitable for Japanese, is less than 60% or 40%, respectively) Known to have HIV antibodies Have a positive result for any of the following: HBs antigen, HBs antibody, HBc antibody, and HCV antibody (this criterion does not apply to a positive test for hepatitis B clearly attributable to hepatitis vaccination) Have serious bacterial/fungal infections Have a serious liver disease (AST [GOT] or ALT[GPT] of ≥ 300 IU) Have a serious renal disease (serum creatinine ≥ 2.0 mg/dL) Have severe heart disease Have active tuberculosis Have any known malignancy or a history of malignancy within the past 5 years Have a history of serious infections Have a history of serious hypersensitivity or anaphylactic reactions to any component of rituximab or to mouse proteins Pregnant, postpartum, and lactating women Refuse to practice contraception from the time of consent to at least 12 months after study completion Have any disease or physical/psychiatric conditions that make study participation difficult/inappropriate Received other investigational products within 12 weeks prior to the study treatment or are participating in other clinical research/studies Smoked within 12 weeks prior to the date of consent Is determined by the investigator (or sub-investigator) to be ineligible for the study for any other reason

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Double-Blind Placebo<br>Participants will receive double-blind matching placebo from baseline until week 24. Participants may then receive open-label rituximab from weeks 24 to 48. | Drug: Double-Blind Placebo<br>* The 4-week treatment period (four 375 mg/m2 doses at 1-week intervals) and subsequent 20-week follow-up period constitute one cycle of treatment. In the double-blind period, one cycle of placebo will be administered. In the active drug period, one additional cycle (rituximab) will be administered.<br>|
| Experimental: Double-Blind Rituximab<br>Participants will receive double-blind rituximab from baseline until week 24. Participants may then receive open-label rituximab from weeks 24 to 48. | Drug: Double-Blind Rituximab<br>* The 4-week treatment period (four 375 mg/m2 doses at 1-week intervals) and subsequent 20-week follow-up period constitute one cycle of treatment. In the double-blind period, one cycle of rituximab will be administered. In the active drug period, one additional cycle (rituximab) will be administered.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Modified Rodnan Total Skin Thickness Score (mRTSS) during double-blind period | Absolute change from pre-treatment observation period in skin sclerosis at week 24 of treatment in the double-blind phase, assessed by mRTSS. mRTSS ranging from 0 (normal) to 3 (severe skin thickening) across 17 different body parts. The total score is the sum of the individual skin scores for all these sites, and ranges from 0 to 51 units. | From baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in percent FVC measured in respiratory function test |  | From baseline to week 24 | 
| Change in percent DLco measured in respiratory function test |  | From baseline to week 24 | 
| Change in TLC measured in respiratory function test |  | From baseline to week 24 | 
| Change in serum levels of KL-6 |  | From baseline to week 24 | 
| Change in serum levels of SP-D |  | From baseline to week 24 | 
| Change in serum levels of SP-A |  | From baseline to week 24 | 
| Change in percentage of interstitial shadow in lungs by high-resolution computed tomography |  | From baseline to week 24 | 
| Change in skin thickness measured following biopsy specimen |  | From baseline to week 24 | 
| Change in HRQOL index measured using MOS 36 Item Short-Form Health Survey |  | From baseline to week 24 | 
| Change in QOL index of SSc patients, assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI) |  | From baseline to week 24 | 
| Change in serum antinuclear antibody titers |  | From baseline to week 24 | 
| Change in serum levels of anti-centromere antibodies |  | From baseline to week 24 | 
| Change in serum levels of anti-Scl-70 antibodies |  | From baseline to week 24 | 
| Change in serum levels of anti-RNA polymerase III antibodies |  | From baseline to week 24 | 
| Change in serum levels of anti-ssDNA antibodies |  | From baseline to week 24 | 
| Change in serum levels of anti-dsDNA antibodies |  | From baseline to week 24 | 
| Change in serum levels of anti-CL antibodies |  | From baseline to week 24 | 
| Change in serum levels of anti-β2-GP1 antibodies |  | From baseline to week 24 | 
| Change in serum levels of lupus anticoagulant |  | From baseline to week 24 | 
| Change in serum levels of anti-SS-A antibodies |  | From baseline to week 24 | 
| Change in serum levels of anti-SS-B antibodies |  | From baseline to week 24 | 
| Change in serum levels of anti-cANCA |  | From baseline to week 24 | 
| Change in serum levels of anti-p-ANCA |  | From baseline to week 24 | 
| Change in serum levels of anti-U1-RNP antibodies |  | From baseline to week 24 | 
| Change in serum levels of IgG |  | From baseline to week 24 | 
| Change in serum levels of IgM |  | From baseline to week 24 | 
| Change in serum levels of IgA |  | From baseline to week 24 | 
| Change in blood CD19+ B cell count |  | From baseline to week 24 | 
| Change in blood CD20+ B cell count |  | From baseline to week 24 | 
| Change in blood CD3+ T cell count |  | From baseline to week 24 | 
| Expression of human anti-rituximab antibodies |  | From baseline to week 24 | 
| Overall incidence, severity, causal relationship, and outcome of adverse events |  | From baseline to week 48 | 
| Incidence of rituximab infusion reactions |  | From baseline to week 48 | 
| PK profile of rituximab: Area under concentration-time curve from time 0 to final observation (AUC0-t) |  | From baseline to week 48 | 
| PK profile of rituximab: maximum serum concentration after dosing (Cmax) |  | From baseline to week 48 | 
| PK profile of rituximab: time to maximum concentration (tmax) |  | From baseline to week 48 | 
| PK profile of rituximab: terminal half-life (t1/2) |  | From baseline to week 48 | 
| PK profile of rituximab: mean residence time |  | From baseline to week 48 | 
| PK profile of rituximab: clearance |  | From baseline to week 48 | 
| PK profile of rituximab: volume of distribution |  | From baseline to week 48 |