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Anti-CD20 Antibodies for Treatment of SLE-PAH

Primary Purpose

Systemic Lupus Erythematosus, Pulmonary Arterial Hypertension

Status
Recruiting
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Rituximab
Sponsored by
Chinese SLE Treatment And Research Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Systemic Lupus Erythematosus focused on measuring anti-CD20 antibodies, Systemic Lupus Erythematosus, Pulmonary Arterial Hypertension, multi-omics

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 1. Subject has provided written informed consent. 2. Subject must be between the ages of 18 and 65, inclusive at the time of recruitment 3. Clinical diagnosis of systemic lupus erythematosus. Diagnosis of SLE-PAH within the past 5 years, with a mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg, PAWP ≤15mmHg, mean PVR of > 3 Wood units at entry. 4. WHO Functional Class II, III, or IV. 5. Subjects must have been treated with background medical therapy for PAH (prostanoid, endothelin receptor antagonist, PDE-5 inhibitor, and/or guanylate cyclase stimulators) for a minimum of 8 weeks and have been on stable dose(s) of those medical therapy(ies) for at least 4 weeks prior to randomization with no expectation of change for 24 weeks after randomization. Exclusion Criteria: 1. Treatment with immunocompromising biologic agents (including, but not limited to TNF inhibitors, anakinra, abatacept, and tocilizumab) within 4 weeks prior to treatment initiation or treatment with infliximab within 8 weeks prior to treatment initiation. 2. SLE combined with important organ damage endangers life: Neuropsychiatric lupus with high risk such as status epilepticus; Refractory thrombocytopenic purpura has a clear bleeding tendency; Pulmonary alveolar hemorrhage leads to respiratory failure; 3. Uncontrolled infection; 4. Severe organ dysfunction: Patients with moderate or severe liver function impairment (Child-Pugh grade B and C); Patients with left ventricular dysfunction (left ventricular ejection fraction<45%); 5. Other diseases are limited to completing a 6-minute walking test: angina pectoris, vascular, musculoskeletal lesions, etc 6. Abnormal laboratory test: platelet<100 × 109/L, or hemoglobin<9 g/dL, or white blood cell count<3 × 109/L, or alanine aminotransferase (ALT)/aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal value, or total bilirubin and blood lipids greater than 2 times the upper limit of normal value 7. Persistent hypotension, i.e. systolic blood pressure (SBP)<90 mmHg 8. PAH caused by any reason other than SLE: other rheumatic diseases (such as SSc, rheumatoid arthritis, dermatomyositis, etc.); Portal hypertension, hereditary hemorrhagic telangiectasia, etc; Congenital heart disease; Suspicious drugs and poisons; 9. Chronic hypoxic disease related pulmonary hypertension: moderate or severe obstructive pulmonary disease: FEV1<55%; Moderate or severe restrictive pulmonary disease: TLC<60%; 10. Chronic thromboembolic pulmonary hypertension: Pulmonary ventilation/perfusion imaging indicates moderate to high suspicion of pulmonary thromboembolism; 11. Existing infections or uncontrollable infections that require antibiotic or antiviral treatment; 12. Women who are breastfeeding or pregnant or who plan to become pregnant during the study; 13. History of malignant tumors in the past 5 years 14. Mental, addictive, or other illnesses that restrict patients from providing informed consent or complying with research requirements; 15. Any condition or treatment that the investigator believes puts the subject at an unacceptable risk as a test participant.

Sites / Locations

  • Peking Union Medical College HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Rituximab group

Arm Description

Rituximab will be administered as two IV infusions of 1000 mg each, given two weeks apart at Day 0 and Week 2. All subjects will receive 40 mg of prednisone orally the night before and morning of each infusion with diphenhydramine and acetaminophen orally thirty to sixty minutes prior to each infusion of rituximab. Subjects will remain on their baseline standard medical regimen.

Outcomes

Primary Outcome Measures

pulmonary vascular resistance (PVR)
PVR as assessed by right heart catheterization, the gold standard method to assess cardiopulmonary haemodynamics. Standardized Fick-based pulmonary vascular resistance (PVRf, in Woods Units) are calculated as follows: PVR = TPG / CO, where TPG = Transpulmonary Gradient (mmHg), CO = Cardiac Output (L/min)

Secondary Outcome Measures

6MWD
The amount of change in 6-minute walking distance (6MWD) from baseline to 24 weeks to evaluate changes in athletic ability
Right atrium Pressure (RAP)
Changes in Right Atrial Pressure (RAP) measured by Right Heart Catheter (RHC) from baseline to 24 weeks. the right atrial (RA) pressure waveform reflects both venous return to the right atrium during ventricular systole and right ventricular end-diastolic pressure. Normal RA pressures range from 0 to 7 mmHg
Cardiac Index (CI)
Changes in Cardiac Index (CI) measured by Right Heart Catheter (RHC) from baseline to 24 weeks. Cardiac Index = Cardiac Output / Body Surface Area. The pulmonary artery catheter (PAC) measures the cardiac output (CO) via either the indicator thermodilution method or the Fick method. Normal hemodynamic measures for CI are 2.8 to 4.2 L/min/m2
Clinical worsening
clinical worsening: includes the first occurrence of any of the following: death, hospitalization due to PAH, increased PAH targeted drugs, deterioration of 6MWD>20%, and deterioration of WHO cardiac function grading.
BNP/NT proBNP
Changes in serological indicators (BNP/NT proBNP) from baseline to 24 weeks. Trending BNP levels can be a useful component of globally assessing the patient's clinical course and monitoring response to treatment. BNP and N-terminal pro-BNP (NT-proBNP) are biomarkers that are commonly used to assess severity and monitor response to therapy in patients with heart failure.
Patients' quality of life
Changes in patients' quality of life as assessed by short form 36 (SF-36) from baseline to 24 and 48 weeks. Short-Form 36 (SF-36) is a self-report health-related quality-of-life (HRQOL) questionnaire, widely used in dialysis patients. It consists of physical and mental component scores (PCS/MCS), ranging from 0 to 100.
SLEDAI
Changes in the SLE Disease Activity Index (SLEDAI) of patients from baseline to 24 weeks. The Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) is a scoring systems for global disease activity, ranging from 0 to105 points. SLEDAI includes 9 modules: neurological involvement, vascular involvement, kidney involvement, musculoskeletal involvement, serosal involvement, skin involvement, immunological abnormalities, systemic symptoms, and hematological involvement.
low-risk stratification
The proportion of patients who met the low risk stratification of the 2022 ESC/ERS pulmonary hypertension guidelines within 24 weeks

Full Information

First Posted
March 28, 2023
Last Updated
June 26, 2023
Sponsor
Chinese SLE Treatment And Research Group
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1. Study Identification

Unique Protocol Identification Number
NCT05828147
Brief Title
Anti-CD20 Antibodies for Treatment of SLE-PAH
Official Title
Efficacy and Mechanism of Anti-CD20 Antibodies in Systemic Lupus Erythematosus Associated Pulmonary Arterial Hypertension Based on Multi Omics Studies
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 25, 2023 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Chinese SLE Treatment And Research Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a prospective, single-arm, single-center, explorative clinical trial to evaluate the effect of Rituximab on disease progression in subjects with SLE-PAH receiving concurrent stable-dose standard medical therapy. The study will focus on assessment of clinical response and safety measures longitudinally. In addition, the biomarker of treatment efficacy with Rituximab and pathogenic autoantibody response in this disease will be investigated.
Detailed Description
This is a prospective, single-arm, single-center, explorative clinical trial to evaluate the effect of Rituximab on disease progression in subjects with SLE-PAH receiving concurrent stable-dose standard medical therapy with a prostanoid, endothelin receptor antagonist, phosphodiesterase 5 (PDE-5) inhibitor, and/or guanylate cyclase stimulators. Objective. The study will focus on assessment of clinical response and safety measures longitudinally.The primary objective of this study is to explore the safety and efficacy of Rituximab in patients with SLE-PAH. In addition, the biomarker of treatment efficacy with Rituximab and pathogenic autoantibody response in this disease will be investigated. Study population. Subjects with SLE-PAH with mean pulmonary artery pressure ≥25mmHg, pulmonary artery wedge pressure ≤15mmHg, and pulmonary vascular resistance > 3WU as measured by right heart catheterization will be enrolled. The diagnosis of SLE-PAH should be confirmed by a rheumatologist experienced in the diagnosis and treatment of systemic lupus erythematosus in conjunction with a cardiologist specializing in management of PAH. Both specialists will be part of the study team at each site. Treatment. Rituximab will be administered as two IV infusions of 1000 mg each, given two weeks apart at Day 0 and Week 2. All subjects will receive 40 mg of prednisone orally the night before and morning of each infusion with diphenhydramine and acetaminophen orally thirty to sixty minutes prior to each infusion of rituximab. Subjects will remain on their baseline standard medical regimen. Fifty eligible subjects will be accrued. Each potential study subject will provide written informed consent prior to screening procedures. All inclusion and exclusion criteria must be met at time of recruitment prior to receipt of the first dose of rituximab (Day 0, Treatment Initiation). Clinical assessments and sample collection will occur regularly through Week 24 with telephone follow-up conducted intermittently. The peripheral proteome, bulk-RNA sequencing, whole exome sequencing, cytokine profile, and T/B cell subsets will be assessed in 0 and Week 24. During this study, AEs and SAEs will be assessed, providing the subject has not withdrawn consent, to capture any infectious event ≥ Grade 3 using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE). No additional study-related data will be collected. The primary efficacy endpoint is the change in pulmonary vascular resistance (PVR) from baseline to 24 weeks after treatment initiation. Hemodynamic measures will be assessed at baseline and Week 24, contributing to the understanding of the relationship between PVR and clinical endpoints. Time to clinical worsening will be assessed as a secondary outcome measure through Week 24, contributing to the understanding of the relationship between PVR and clinical endpoints. Initiation of new therapy due to disease worsening prior to Week 24 will prompt an endpoint visit and right heart catheterization prior to initiation of the new therapy. The mechanistic study objective is to identify biomarkers which correlate with treatment response as measured by exercise capacity (6MWD) and PVR (right heart catheterization). Proteomics, whole exome sequencing, cytokine profile,TB cell subsets, and bulk-RNA sequencing will be measured before and after rituximab treatment. The other mechanistic objective is to determine if the biomarkers anti-U1 RNP, anti-cardiolipin, and other autoantibodies, and quantitative immunoglobulin levels, including IgG subclasses, correlate with treatment response as measured by PVR (right heart catheterization). The total duration of the study is anticipated to be approximately 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Systemic Lupus Erythematosus, Pulmonary Arterial Hypertension
Keywords
anti-CD20 antibodies, Systemic Lupus Erythematosus, Pulmonary Arterial Hypertension, multi-omics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Model Description
single-arm, all patients will receive anti-CD20 antibodies.
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Rituximab group
Arm Type
Experimental
Arm Description
Rituximab will be administered as two IV infusions of 1000 mg each, given two weeks apart at Day 0 and Week 2. All subjects will receive 40 mg of prednisone orally the night before and morning of each infusion with diphenhydramine and acetaminophen orally thirty to sixty minutes prior to each infusion of rituximab. Subjects will remain on their baseline standard medical regimen.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Hanlikang
Intervention Description
Rituximab will be administered as two IV infusions of 1000 mg each, given two weeks apart at Day 0 and Week 2. All subjects will receive 40 mg of prednisone orally the night before and morning of each infusion with diphenhydramine and acetaminophen orally thirty to sixty minutes prior to each infusion of rituximab. Subjects will remain on their baseline standard medical regimen.
Primary Outcome Measure Information:
Title
pulmonary vascular resistance (PVR)
Description
PVR as assessed by right heart catheterization, the gold standard method to assess cardiopulmonary haemodynamics. Standardized Fick-based pulmonary vascular resistance (PVRf, in Woods Units) are calculated as follows: PVR = TPG / CO, where TPG = Transpulmonary Gradient (mmHg), CO = Cardiac Output (L/min)
Time Frame
0-24 weeks
Secondary Outcome Measure Information:
Title
6MWD
Description
The amount of change in 6-minute walking distance (6MWD) from baseline to 24 weeks to evaluate changes in athletic ability
Time Frame
0-24 weeks
Title
Right atrium Pressure (RAP)
Description
Changes in Right Atrial Pressure (RAP) measured by Right Heart Catheter (RHC) from baseline to 24 weeks. the right atrial (RA) pressure waveform reflects both venous return to the right atrium during ventricular systole and right ventricular end-diastolic pressure. Normal RA pressures range from 0 to 7 mmHg
Time Frame
0-24 weeks
Title
Cardiac Index (CI)
Description
Changes in Cardiac Index (CI) measured by Right Heart Catheter (RHC) from baseline to 24 weeks. Cardiac Index = Cardiac Output / Body Surface Area. The pulmonary artery catheter (PAC) measures the cardiac output (CO) via either the indicator thermodilution method or the Fick method. Normal hemodynamic measures for CI are 2.8 to 4.2 L/min/m2
Time Frame
0-24 weeks
Title
Clinical worsening
Description
clinical worsening: includes the first occurrence of any of the following: death, hospitalization due to PAH, increased PAH targeted drugs, deterioration of 6MWD>20%, and deterioration of WHO cardiac function grading.
Time Frame
0-24 weeks
Title
BNP/NT proBNP
Description
Changes in serological indicators (BNP/NT proBNP) from baseline to 24 weeks. Trending BNP levels can be a useful component of globally assessing the patient's clinical course and monitoring response to treatment. BNP and N-terminal pro-BNP (NT-proBNP) are biomarkers that are commonly used to assess severity and monitor response to therapy in patients with heart failure.
Time Frame
0-24 weeks
Title
Patients' quality of life
Description
Changes in patients' quality of life as assessed by short form 36 (SF-36) from baseline to 24 and 48 weeks. Short-Form 36 (SF-36) is a self-report health-related quality-of-life (HRQOL) questionnaire, widely used in dialysis patients. It consists of physical and mental component scores (PCS/MCS), ranging from 0 to 100.
Time Frame
0-24 weeks
Title
SLEDAI
Description
Changes in the SLE Disease Activity Index (SLEDAI) of patients from baseline to 24 weeks. The Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) is a scoring systems for global disease activity, ranging from 0 to105 points. SLEDAI includes 9 modules: neurological involvement, vascular involvement, kidney involvement, musculoskeletal involvement, serosal involvement, skin involvement, immunological abnormalities, systemic symptoms, and hematological involvement.
Time Frame
0-24 weeks
Title
low-risk stratification
Description
The proportion of patients who met the low risk stratification of the 2022 ESC/ERS pulmonary hypertension guidelines within 24 weeks
Time Frame
0-24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 1. Subject has provided written informed consent. 2. Subject must be between the ages of 18 and 65, inclusive at the time of recruitment 3. Clinical diagnosis of systemic lupus erythematosus. Diagnosis of SLE-PAH within the past 5 years, with a mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg, PAWP ≤15mmHg, mean PVR of > 3 Wood units at entry. 4. WHO Functional Class II, III, or IV. 5. Subjects must have been treated with background medical therapy for PAH (prostanoid, endothelin receptor antagonist, PDE-5 inhibitor, and/or guanylate cyclase stimulators) for a minimum of 8 weeks and have been on stable dose(s) of those medical therapy(ies) for at least 4 weeks prior to randomization with no expectation of change for 24 weeks after randomization. Exclusion Criteria: 1. Treatment with immunocompromising biologic agents (including, but not limited to TNF inhibitors, anakinra, abatacept, and tocilizumab) within 4 weeks prior to treatment initiation or treatment with infliximab within 8 weeks prior to treatment initiation. 2. SLE combined with important organ damage endangers life: Neuropsychiatric lupus with high risk such as status epilepticus; Refractory thrombocytopenic purpura has a clear bleeding tendency; Pulmonary alveolar hemorrhage leads to respiratory failure; 3. Uncontrolled infection; 4. Severe organ dysfunction: Patients with moderate or severe liver function impairment (Child-Pugh grade B and C); Patients with left ventricular dysfunction (left ventricular ejection fraction<45%); 5. Other diseases are limited to completing a 6-minute walking test: angina pectoris, vascular, musculoskeletal lesions, etc 6. Abnormal laboratory test: platelet<100 × 109/L, or hemoglobin<9 g/dL, or white blood cell count<3 × 109/L, or alanine aminotransferase (ALT)/aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal value, or total bilirubin and blood lipids greater than 2 times the upper limit of normal value 7. Persistent hypotension, i.e. systolic blood pressure (SBP)<90 mmHg 8. PAH caused by any reason other than SLE: other rheumatic diseases (such as SSc, rheumatoid arthritis, dermatomyositis, etc.); Portal hypertension, hereditary hemorrhagic telangiectasia, etc; Congenital heart disease; Suspicious drugs and poisons; 9. Chronic hypoxic disease related pulmonary hypertension: moderate or severe obstructive pulmonary disease: FEV1<55%; Moderate or severe restrictive pulmonary disease: TLC<60%; 10. Chronic thromboembolic pulmonary hypertension: Pulmonary ventilation/perfusion imaging indicates moderate to high suspicion of pulmonary thromboembolism; 11. Existing infections or uncontrollable infections that require antibiotic or antiviral treatment; 12. Women who are breastfeeding or pregnant or who plan to become pregnant during the study; 13. History of malignant tumors in the past 5 years 14. Mental, addictive, or other illnesses that restrict patients from providing informed consent or complying with research requirements; 15. Any condition or treatment that the investigator believes puts the subject at an unacceptable risk as a test participant.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mengtao Li, Prof
Phone
86-10-69159958
Email
mengtao.li@cstar.org.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Yufang Ding, MD
Phone
86-10-69159958
Email
54dingyufang@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mengtao Li, Prof
Organizational Affiliation
Peking Union Medical College Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Peking Union Medical College Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100730
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Junyan Qian, MD
Phone
86-10-69159958
First Name & Middle Initial & Last Name & Degree
Yufang Ding, MD
Phone
86-10-69159958

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
study protocol and statistical analysis plan
IPD Sharing Time Frame
2025.12-2027.12
IPD Sharing Access Criteria
open access
Citations:
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Citation
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Results Reference
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23963101
Citation
Li M, Zhang W, Leng X, Li Z, Ye Z, Li C, Li X, Zhu P, Wang Z, Zheng Y, Li X, Zhang M, Zhang F, Zhao Y, Zeng X; CSTAR co-authors. Chinese SLE Treatment and Research group (CSTAR) registry: I. Major clinical characteristics of Chinese patients with systemic lupus erythematosus. Lupus. 2013 Oct;22(11):1192-9. doi: 10.1177/0961203313499086. Epub 2013 Aug 20.
Results Reference
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PubMed Identifier
30635295
Citation
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Results Reference
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PubMed Identifier
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Citation
Gomez Mendez LM, Cascino MD, Garg J, Katsumoto TR, Brakeman P, Dall'Era M, Looney RJ, Rovin B, Dragone L, Brunetta P. Peripheral Blood B Cell Depletion after Rituximab and Complete Response in Lupus Nephritis. Clin J Am Soc Nephrol. 2018 Oct 8;13(10):1502-1509. doi: 10.2215/CJN.01070118. Epub 2018 Aug 8. Erratum In: Clin J Am Soc Nephrol. 2019 Jan 7;14(1):111.
Results Reference
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PubMed Identifier
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Citation
Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003 Aug;22(2):358-63. doi: 10.1183/09031936.03.00038903.
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PubMed Identifier
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Citation
Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Radegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2023 Jan 6;61(1):2200879. doi: 10.1183/13993003.00879-2022. Print 2023 Jan. No abstract available.
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Results Reference
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Anti-CD20 Antibodies for Treatment of SLE-PAH

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