Tocilizumab and Tofacitinib in the Treatment of Vascular Behçet's Syndrome

Official title

Efficacy and Safety of Tocilizumab and Tofacitinib in the Treatment of Patients With Vascular Behçet's Syndrome

Overview

This project aims to evaluate the efficacy and safety of the combination of glucocorticoids with tocilizumab or tofacitinib, compared to the traditional combination of glucocorticoids with cyclophosphamide in the treatment of vascular Behçet's syndrome.

Detailed description

Behçet's Syndrome (BS) is a recurrent and systemic vasculitis, with an incidence rate of about 14/100,000 in China, higher than that in Europe and America. Vascular Behcet's Syndrome (VBS) is an important subtype of BS characterized by multiple venous and artery lesions. It affects 20-25% of BS patients, predominantly young adult males, and is the leading cause of mortality in BS patients (67%), especially in patients with aneurysms. Therefore, exploring the diagnosis and treatment strategies for VBS is key to improving the prognosis of BS.

This project aims to investigate the efficacy and safety of the combination of glucocorticoids (GCS) with the biologic agent tocilizumab or the targeted small molecule tofacitinib, compared to the combination of GCS with cyclophosphamide in the treatment of VBS aneurysms, as well as to screen for biomarkers related to the response of tocilizumab or tofacitinib, and to improve the assessment and treatment of VBS and establish a precision diagnosis and treatment strategy.

This is a Phase IIb, multi-center, randomized, open-label, GCS plus cyclophosphamide-controlled, parallel design, prospective clinical study. Patients will be randomly assigned to three groups in a 1:1:1 ratio (tocilizumab + GCS vs tofacitinib + GCS vs cyclophosphamide + GCS, 27:27:27) after screening and recruitment. Patients will be followed up every 4 weeks from weeks 0-12, and every 6 weeks from weeks 12-24. The primary endpoint is the complete remission (CR) rate at the 12th-week follow-up. All participants will undergo their final visit at 24 weeks.

Interventions

• Drug tocilizumab
  Participants will receive intravenous infusion of tocilizumab 8mg/kg every 4 weeks for 24 weeks.
• Drug tofacitinib
  Participants will receive tofacitinib 5mg twice a day for 24 weeks of treatment.
• Drug cyclophosphamide
  Participants will receive intravenous infusion of cyclophosphamide 0.5g biweekly for 24 weeks.

Primary outcome measures

• The primary endpoint is the complete response (CR) rate at week 12. [Time frame: Baseline to week 12]

Secondary outcome measures (8)

• The secondary endpoints include CR rate at week 24, and partial response (PR) rate at week 12/24. [Time frame: Baseline to week 24]
• Change From Baseline in Disease Activity as Measured by Behçet's Disease Current Activity Form (BDCAF). [Time frame: BDCAF were assessed at weeks 0, 4, 8, 12, 18, and 24]
• Change From Baseline in the degree of vasculitis damage as Measured by Behçet's syndrome Overall Damage Index (BODI). [Time frame: BODI were assessed at weeks 0 and 24]
• 4.Change From Baseline in the degree of vasculitis damage as Measured by Vasculitis Damage Index (VDI). [Time frame: Time Frame: VDI were assessed at weeks 0, 12, and 24]
• Change From Baseline in ESR and hs-CRP. [Time frame: ESR and hs-CRP were assessed at weeks 0, 4, 8, 12, 18, and 24]
• 6.Change From Baseline in imaging changes including vascular ultrasonography, and CTA (including progression, improvement, and stability) [Time frame: Imaging examinations were assessed at weeks 0, 12 and 24]
• 7.Change From Baseline in 36 health survey questionnaire (SF-36). [Time frame: SF-36 were assessed at weeks 0, 12, and 24]
• Safety assessment: Record the types, frequency, and severity of adverse events, as well as the number of study participants who were discontinued due to any adverse events. [Time frame: Adverse events were assessed at weeks 0, 4, 8, 12, 18, and 24]

Eligibility criteria

Inclusion criteria

1． Understand and voluntarily sign an informed consent form prior to any study-related assessments/procedures being conducted.

2\. Male and female subjects aged 18-65 years.

3． Fulfill the 2013 International Classification Criteria for Behcet's Disease (ICBD).

4． Patients with aneurysmal dilatation/aneurysm of the descending aorta and/or peripheral arteries confirmed by ultrasonography and/or computed tomography angiography (CTA).

5\. Elevated acute phase reactants ESR and hs-CRP.

Exclusion criteria

• Cardiovascular manifestations that cannot be distinguished from giant cell arteritis, Burger's disease, or atherosclerotic aneurysm; infectious aneurysm;
• Other active organ involvement related to BS that requires intensified immunosuppressive treatment, including gastrointestinal ulcers, uveitis, and parenchymal neurological involvement;
• Patients with severe aneurysms requiring emergency intervention surgery; patients with elective surgery indications require the consensus between rheumatologists and vascular surgeons to determine inclusion or exclusion.
• Severe organ dysfunction, including ALT, AST, and TBIL exceeding the upper limit of normal by more than 2 times, serum creatinine ≥ 133 mmol/L, white blood cell count < 3×10\^9/L, ANC < 2×10\^9/L, hemoglobin < 80g/L, platelet count < 100×10\^9/L;
• Active infection such as active tuberculosis, hepatitis B or C, syphilis, chronic EBV infection, persistent or severe bacterial or viral infection;
• Primary or secondary immunodeficiency;
• Malignant tumor;
• Use of immunosuppressants such as Cyclosporin A (CsA), Azathioprine (AZA), Tacrolimus (TAC), Mycophenolate Mofetil (MMF), or Cyclophosphamide (CTX) within 1 month;
• Use of biologics/small molecule drugs within 5 half-lives (baricitinib within 10 days; etanercept within 4 weeks; infliximab within 8 weeks; adalimumab, golimumab, ustekinumab, and abatacept within 10 weeks, secukinumab within 6 months, and previously use of tocilizumab and tofacitinib);
• Pregnant, lactating, or planning a recent pregnancy;
• Subjects who do not agree to or are unable to comply with regular visits.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking Union Medical College Hospital — Beijing

Identifiers

NCT: NCT05845723 · TCZ/TOF-VBS-PUMCH

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗