Clinical trial NCT05828147: 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
Overall status: RECRUITING
Phase: PHASE4
Conditions: Systemic Lupus Erythematosus
Pulmonary Arterial Hypertension
Keywords: anti-CD20 antibodies
Systemic Lupus Erythematosus
Pulmonary Arterial Hypertension
multi-omics
Lead sponsor: Chinese SLE Treatment And Research Group
Sponsor class: OTHER
First posted: 2023-04-25
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single-arm, all patients will receive anti-CD20 antibodies.
Primary purpose: TREATMENT

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.

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:

  1. Neuropsychiatric lupus with high risk such as status epilepticus;
  2. Refractory thrombocytopenic purpura has a clear bleeding tendency;
  3. Pulmonary alveolar hemorrhage leads to respiratory failure;
* 3. Uncontrolled infection;
* 4. Severe organ dysfunction:

  1. Patients with moderate or severe liver function impairment (Child-Pugh grade B and C);
  2. 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.

Primary outcomes:
measure: pulmonary vascular resistance (PVR)
timeFrame: 0-24 weeks
Secondary outcomes:
measure: 6MWD
timeFrame: 0-24 weeks
measure: Right atrium Pressure (RAP)
timeFrame: 0-24 weeks
measure: Cardiac Index (CI)
timeFrame: 0-24 weeks
measure: Clinical worsening
timeFrame: 0-24 weeks
measure: BNP/NT proBNP
timeFrame: 0-24 weeks
measure: Patients' quality of life
timeFrame: 0-24 weeks
measure: SLEDAI
timeFrame: 0-24 weeks
measure: low-risk stratification
timeFrame: 0-24 weeks
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
Study officials:
affiliation: Peking Union Medical College Hospital
name: Mengtao Li, Prof
role: PRINCIPAL_INVESTIGATOR
References:
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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.
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