A Pilot Study in Severe Patients With Takayasu Arteritis.

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Brief Title

A Pilot Study in Severe Patients With Takayasu Arteritis.

Official Title

A Pilot Study in the Treatment of Severe Patients With Takayasu Arteritis With Tocilizumab and Adalimumab, Based on ECTA Cohort

Brief Summary

      Takayasu arteritis (TAK) is a rare chronic inflammatory arteritis, which lacks an effective
      well-accepted intervention strategy. We classify TAK patients into 3 levels, including mild,
      moderate, and severe. And the biological agents tocilizumab and adalimumab are randomly
      prescribed in severe patients, to find out the relatively better treatment strategy,
      facilitating better intervention strategy in severe TAK patients.
    

Detailed Description

      The Takayasu arteritis (TAK) is a rare chronic inflammatory arteritis, which lacks an
      effective well-accepted intervention strategy. Previous studies have revealed that
      methotrexate, tofacitinib, adalimumab, and tocilizumab were effective in controlling disease
      activity and preventing disease relapse in some TAK patients, especially the latter two
      biological agents. However, we believed that different patients should be prescribed
      different drug combinations, i.e. personalized medicine, to obtain the optimal intervention
      effect.

      Here we tried to classify the TAK patients into three levels including mild, moderate, and
      severe, and prescribe different drug interventions to discover which biological agent is
      better in severe TAK patients.

      1. Patients were classified as mild, moderate, and severe groups according to the disease
      severity of TAK patients.

      1.1 Severe

        1. Severe hypertension

             1. Continuously upper limb systolic blood pressure ≥180mmHg or diastolic blood
                pressure ≥110mmHg;

             2. OR upper limb blood pressure cannot be measured if lower limb systolic blood
                pressure ≥200mmHg or diastolic blood pressure ≥120mmHg;

             3. With target organ damage due to hypertension;

        2. Aortic arch and its branches involved

           a. Multiple branches involved (two or more) and severe stenosis (stenosis rate ≥70%); b.
           stenosis rate ≥50%, accompanied by nervous system ischemic symptoms and/or signs; c.
           stenosis rate ≥50%, accompanied by a recent history of cerebrovascular events;

        3. The carotid artery and its branches involved

             1. Multiple branches (two or more) involved and severe stenosis (stenosis rate ≥70%);

             2. stenosis rate ≥50%, accompanied by nervous system ischemic symptoms and/or signs;

             3. stenosis rate ≥50%, accompanied by the recent history of cerebrovascular events;

        4. Pulmonary artery involvement

           a. Chest tightness, hemoptysis, dyspnea, radionuclide pulmonary ventilation/blood
           perfusion imaging or CTA suggesting pulmonary artery thrombosis with respiratory failure
           (type I); b. Chest tightness, shortness of breath, and cardiac ultrasound suggesting
           severe pulmonary artery hypertension with cardiac function abnormality (NYHA class III
           and above);

        5. The coronary artery involved

             1. The onset of unstable angina pectoris or myocardial infarction;

             2. Cardiac ultrasound indicating ischemic cardiomyopathy, NYHA class III and above;

        6. The aortic valve and aortic root involved

             1. Severe reflux of the aortic valve;

             2. OR aortic valve leakage, annulus tearing;

             3. OR aneurysm in the aortic root and/or ascending aortic (≥2 times in diameter);

             4. OR dilation of the aortic root and/or ascending aorta (≥5cm in diameter);

             5. OR dissection of the aortic root and/or ascending aorta; Any item of the above a -
                e is accompanied by abnormal cardiac function (NYHA III and above);

        7. Renal artery involved a. Severe stenosis of renal artery secondary to malignant
           hypertension (blood pressure is still 180 / 120mmHg after treatment with three or more
           antihypertensive drugs) b. Severe renal artery stenosis accompanied by a progressive
           increase in serum creatinine or a reduction in glomerular filtration rate (GFR) of ≥25%;

        8. Glucocorticoids and the traditional synthetic chemical immunosuppressants were of no
           use. And the disease is not well controlled with the severe injury of the organs.

      1.2 Moderate

        1. Hypertension

           a. Upper limb systolic blood pressure ≥160-180mmHg or / and diastolic blood pressure
           ≥100-110mmHg; b. OR upper limb blood pressure is unmeasurable or lower limb systolic
           blood pressure is ≥180mmHg or diastolic blood pressure is ≥100-110mmHg;

        2. Aortic arch and its branches involved

           a. 1-2 vessels are involved with moderate stenosis (stenosis rate ≥50%-<70%); b.
           Dizziness occurs during physical activity, and symptoms disappear in the resting state;

        3. The carotid artery and its branches involved

           a. Unilateral or bilateral vascular stenosis rate ≥50% -70%, with dizziness during light
           physical activity;

        4. Pulmonary artery involved

           a. Radionuclide pulmonary ventilation/blood perfusion imaging or CTA indicates pulmonary
           vascular disease; chest tightness after activity; Cardiac ultrasound indicates moderate
           pulmonary artery hypertension (pressure> 40-60mmHg), with abnormal cardiac function
           (NYHA class Ⅱ);

        5. Coronary artery involvement

           a. Chest tightness and chest pain after moderate activities, CTA showed 50% or more in
           coronary artery stenosis, abnormal cardiac function (NYHA class Ⅱ);

        6. The aortic valve and aortic root involved

             1. Moderate aortic regurgitation;

             2. Aortic root and/or ascending aortic aneurysm (diameter <2 times);

             3. Dilation of the aortic root and/or ascending aorta (diameter <5cm); Each item of a
                - c is accompanied by abnormal cardiac function (NYHA Class II);

        7. Renal artery involvement a. Renal artery stenosis rate ≥50%, and blood pressure 160-180
           / 110-120 (excluding 120) mmHg after treatment, or with left ventricular myocardial
           hypertrophy, hypertension and heart disease, CKD-II;

      1.3 Mild

        1. Hypertension

             1. Upper limb systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg;

             2. OR upper limb blood pressure is unmeasurable or lower limb systolic blood pressure
                is ≥140mmHg or diastolic blood pressure is ≥90mmHg;

        2. Aortic arch and its branches involved a. Single or multiple lesions with mild stenosis
           (stenosis rate <50%), and without neurological ischemic symptoms and/or signs in daily
           activities;

        3. The carotid artery and its branches involved

           a. Single or multiple lesions with mild stenosis (stenosis rate <50%) and no
           neurological ischemic symptoms and/or signs during daily activities;

        4. The pulmonary artery involved

             1. Cardiac ultrasound indicates mild or normal pulmonary artery pressure (pressure
                30-40mmHg);

             2. Imaging shows pulmonary arteritis or pulmonary artery stenosis, occlusion a and b,
                with chest tightness, shortness of breath, and hemoptysis without activity; cardiac
                function (NYHA I), normal blood gas analysis;

        5. The coronary artery involved

           a. Chest tightness, shortness of breath, chest pain after inactivity; cardiac function
           (NYHA I);

        6. The aortic valve and aortic root involved

             1. Mild aortic regurgitation;

             2. Aortic root and / or ascending aortic aneurysm-like expansion (diameter <1.5
                times); a and b, each with cardiac function (NYHA I);

        7. Renal artery involved a. Renal artery stenosis rate <50%, without/with mild hypertension
           (see 1), or normal serum creatinine, normal or slightly impaired glomerular filtration
           rate (GFR);

      1.2. Based on the TAK patients in the ECTA cohort (Clinical trials. No: NCT03893136), we
      tried to compare the treatment efficacy of biological agents between tocilizumab (TCZ) and
      adalimumab (ADA) in severe TAK patients, with a pilot study.

      Other important detailed description of the study are listed as follows:

        1. Basic treatment of prednisone:

           The initial prednisone dose is 40mg.qd.po, and maintained for 1 month. After 1 month's
           treatment, the dose is gradually tapered to 15mg by 5mg per 2 weeks. Subsequently, the
           dose is decreased to 5mg by 2.5mg per 3 months. The 5mg is the final target maintained
           dose. In the treatment, if the relapse occurs, the dose of prednisone returned to the
           last dosage. For example, if the patient gets a relapse at the dose of 15mg of
           prednisone, then the dose of prednisone returned to 20mg.

           The relapse of TAK is defined according to the "2018 Update of the EULAR recommendations
           for the management of large vessel vasculitis". Relapse includes major relapse or minor
           relapse. Major relapse: Recurrence of active disease with either of the following: a.
           Clinical features of ischemia* (including jaw claudication, visual symptoms, the visual
           loss attributable to TAK, scalp necrosis, stroke, limb claudication). b. Evidence of
           active aortic inflammation resulting in progressive aortic or large vessel dilatation,
           stenosis or dissection. Minor relapse Recurrence of active disease, not fulfilling the
           criteria for the major relapse.

        2. ADA: 40mg bim IH.

        3. TCZ: 8mg/kg qm ivgtt.

        4. Treatment shift: if the TAK patients in ADA group failed to reach clinical remission at
           the end of 24th week, they would be shifted to TCZ group starting a new round of
           induction and complete the rest 24-week follow-up; and vice versa;

      In the follow-up, the disease remission and related markers are monitored.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Disease remission at 24 weeks.

Secondary Outcome

 Disease remission at 48 weeks.

Condition

Takayasu Arteritis

Intervention

Tocilizumab

Study Arms / Comparison Groups

 Tocilizumab
Description:  This group of 20 TAK cases are prescribed with tocilizumab (Dose: 8mg/kg. qm. ivgtt.) for 24 weeks.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

40

Start Date

March 1, 2020

Completion Date

December 31, 2023

Primary Completion Date

May 1, 2022

Eligibility Criteria

        Inclusion Criteria:

          1. age≥14 years old;

          2. active: Kerr score≥ 2;

          3. severe:

               1. Blood pressure > 180/110mmHg;

               2. ≥ 3 branches with the stenotic rate > 70% involved;

               3. high degree of organ insufficiency: NYHF III~IV; eGFR (MRDR) 15~ 60ml/min;

        Exclusion Criteria:

          1. Severe organ insufficiency;

          2. Acute or chronic active infections including tuberculosis, hepatitis virus, etc.;

          3. Other autoimmune diseases including systemic lupus erythematosus, Behcet disease, IgG4
             relative disease;

          4. malignant tumors;

          5. history of severe drug allergy;

          6. successive twice relapse occurs even after the intervention adjustment ( for the
             benefits of patients)
      

Gender

All

Ages

14 Years - 100 Years

Accepts Healthy Volunteers

No

Contacts

Lindi Jiang, PhD, +8615221160538, [email protected]

Location Countries

China

Location Countries

China

Administrative Informations


NCT ID

NCT04300686

Organization ID

TACTIC-SS


Responsible Party

Sponsor

Study Sponsor

Shanghai Zhongshan Hospital


Study Sponsor

Lindi Jiang, PhD, Study Chair, Fudan University


Verification Date

March 2020