Clinical trial NCT04274257: A Study of the Efficacy and Safety of Rituximab in Participants With Systemic Sclerosis
Official title: Double-Blind, Parallel-group Comparison, Investigators Initiated Phase II Clinical Trial of IDEC-C2B8 (Rituximab) in Patients With Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Scleroderma, Systemic
Skin Sclerosis
Lung Fibrosis
Autoimmune Diseases
Collagen Diseases
Lead sponsor: Tokyo University
Sponsor class: OTHER
Collaborators: name: Japan Agency for Medical Research and Development
name: Zenyaku Kogyo Co., Ltd.
First posted: 2020-02-18
Enrollment: 56
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. 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
2. Aged 20 or older and younger than 80 at the time of consent
3. Have an expected survival of at least 6 months (and expected to allow 6 months of observation)
4. 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.
5. Provided written consent to participate in the study

Exclusion Criteria:

1. 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.
2. 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.
3. 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)
4. Known to have HIV antibodies
5. 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)
6. Have serious bacterial/fungal infections
7. Have a serious liver disease (AST \[GOT\] or ALT\[GPT\] of ≥ 300 IU)
8. Have a serious renal disease (serum creatinine ≥ 2.0 mg/dL)
9. Have severe heart disease
10. Have active tuberculosis
11. Have any known malignancy or a history of malignancy within the past 5 years
12. Have a history of serious infections
13. Have a history of serious hypersensitivity or anaphylactic reactions to any component of rituximab or to mouse proteins
14. Pregnant, postpartum, and lactating women
15. Refuse to practice contraception from the time of consent to at least 12 months after study completion
16. Have any disease or physical/psychiatric conditions that make study participation difficult/inappropriate
17. Received other investigational products within 12 weeks prior to the study treatment or are participating in other clinical research/studies
18. Smoked within 12 weeks prior to the date of consent
19. Is determined by the investigator (or sub-investigator) to be ineligible for the study for any other reason

Primary outcomes:
measure: Change in Modified Rodnan Total Skin Thickness Score (mRTSS) during double-blind period
timeFrame: From baseline to week 24
Secondary outcomes:
measure: Change in percent FVC measured in respiratory function test
timeFrame: From baseline to week 24
measure: Change in percent DLco measured in respiratory function test
timeFrame: From baseline to week 24
measure: Change in TLC measured in respiratory function test
timeFrame: From baseline to week 24
measure: Change in serum levels of KL-6
timeFrame: From baseline to week 24
measure: Change in serum levels of SP-D
timeFrame: From baseline to week 24
measure: Change in serum levels of SP-A
timeFrame: From baseline to week 24
measure: Change in percentage of interstitial shadow in lungs by high-resolution computed tomography
timeFrame: From baseline to week 24
measure: Change in skin thickness measured following biopsy specimen
timeFrame: From baseline to week 24
measure: Change in HRQOL index measured using MOS 36 Item Short-Form Health Survey
timeFrame: From baseline to week 24
measure: Change in QOL index of SSc patients, assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI)
timeFrame: From baseline to week 24
measure: Change in serum antinuclear antibody titers
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-centromere antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-Scl-70 antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-RNA polymerase III antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-ssDNA antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-dsDNA antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-CL antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-β2-GP1 antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of lupus anticoagulant
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-SS-A antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-SS-B antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-cANCA
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-p-ANCA
timeFrame: From baseline to week 24
measure: Change in serum levels of anti-U1-RNP antibodies
timeFrame: From baseline to week 24
measure: Change in serum levels of IgG
timeFrame: From baseline to week 24
measure: Change in serum levels of IgM
timeFrame: From baseline to week 24
measure: Change in serum levels of IgA
timeFrame: From baseline to week 24
measure: Change in blood CD19+ B cell count
timeFrame: From baseline to week 24
measure: Change in blood CD20+ B cell count
timeFrame: From baseline to week 24
measure: Change in blood CD3+ T cell count
timeFrame: From baseline to week 24
measure: Expression of human anti-rituximab antibodies
timeFrame: From baseline to week 24
measure: Overall incidence, severity, causal relationship, and outcome of adverse events
timeFrame: From baseline to week 48
measure: Incidence of rituximab infusion reactions
timeFrame: From baseline to week 48
measure: PK profile of rituximab: Area under concentration-time curve from time 0 to final observation (AUC0-t)
timeFrame: From baseline to week 48
measure: PK profile of rituximab: maximum serum concentration after dosing (Cmax)
timeFrame: From baseline to week 48
measure: PK profile of rituximab: time to maximum concentration (tmax)
timeFrame: From baseline to week 48
measure: PK profile of rituximab: terminal half-life (t1/2)
timeFrame: From baseline to week 48
measure: PK profile of rituximab: mean residence time
timeFrame: From baseline to week 48
measure: PK profile of rituximab: clearance
timeFrame: From baseline to week 48
measure: PK profile of rituximab: volume of distribution
timeFrame: From baseline to week 48
Other outcomes:
Locations:
city: Fukui
country: Japan
facility: University of Fukui Hospital
city: Nagoya
country: Japan
facility: Chukyo Hospital
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
city: Tsukuba
country: Japan
facility: University of Tsukuba Hospital
Study officials:
affiliation: Tokyo University
name: Ayumi Yoshizaki, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ebata S, Oba K, Kashiwabara K, Ueda K, Uemura Y, Watadani T, Fukasawa T, Miura S, Yoshizaki-Ogawa A, Yoshihide A, Yoshizaki A, Sato S. Predictors of rituximab effect on modified Rodnan skin score in systemic sclerosis: a machine-learning analysis of the DesiReS trial. Rheumatology (Oxford). 2022 Nov 2;61(11):4364-4373. doi: 10.1093/rheumatology/keac023.