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

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

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.

Study Overview

• Status: Completed
• Conditions: Autoimmune Diseases; Collagen Diseases; Scleroderma, Systemic; Lung Fibrosis; Skin Sclerosis
• Intervention / Treatment: Drug: Double-Blind Placebo; Drug: Double-Blind Rituximab

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Japan
  • Fukui, Japan
    • University of Fukui Hospital
  • Nagoya, Japan
    • Chukyo Hospital
  • Tokyo, Japan, 113-8655
    • The University of Tokyo Hospital
  • Tsukuba, Japan
    • University of Tsukuba Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Double-Blind Placebo; 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; 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.
Experimental: Double-Blind Rituximab; 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; 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.

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	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

Collaborators and Investigators

• Sponsor: Tokyo University
• Collaborators: Japan Agency for Medical Research and Development; Zenyaku Kogyo Co., Ltd.
• Investigators: Principal Investigator: Ayumi Yoshizaki, MD, PhD, Tokyo University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2017
• Primary Completion (Actual): May 9, 2019
• Study Completion (Actual): November 5, 2019

Study Registration Dates

• First Submitted: February 13, 2020
• First Submitted That Met QC Criteria: February 15, 2020
• First Posted (Actual): February 18, 2020

Study Record Updates

• Last Update Posted (Actual): February 18, 2020
• Last Update Submitted That Met QC Criteria: February 15, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse; Pulmonary Fibrosis; Collagen Diseases; Autoimmune Diseases; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: 2017019-11DX

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes