Efficiency of Methotrexate and Tofacitinib in Mild and Moderate Patients

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Brief Title

Efficiency of Methotrexate and Tofacitinib in Mild and Moderate Patients

Official Title

Randomized Open-label Study in Mild and Moderate Patients With Takayasu Arteritis Between Methotrexate and Tofacitinib Based on the ECTA Cohort.

Brief Summary

      Takayasu arteritis (TAK) is a rare chronic inflammatory arteritis, which lacks an effective
      well-accepted intervention strategy. Here we tried to classify TAK patients in 3 levels,
      including mild, moderate, and severe, and prescribe methotrexate and tofacitinib randomly in
      mild and moderate patients, to observe the relatively better treatment strategy, facilitating
      better intervention strategy in TAK patients.
    

Detailed Description

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

      So, here we tried to classify the TAK patients into three levels, and prescribe different
      drug interventions to discover the relatively better treatment strategy.

      1. Patients were classified as mild, moderate and severe group 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 recent history of cerebrovascular events;

        3. 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 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. Coronary artery involved

             1. Onset of unstable angina pectoris or myocardial infarction;

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

        6. Aortic valve and aortic root involved

             1. Severe reflux of the aortic valve;

             2. OR aortic valve leakage, annulus tearing;

             3. OR aneurysm in 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 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. 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. 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. 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. Pulmonary artery involved

           a. Cardiac ultrasound indicates mild or normal pulmonary artery pressure (pressure
           30-40mmHg); b. 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. Coronary artery involved

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

        6. 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);

      2. Based on the TAK patients in the ECTA cohort (Clinical trials. No: NCT03893136), we tried
      to compare the treatment efficacy between Tofacitinib (TOF) and methotrexate (MTX) in mild
      and moderate patients, with a randomized open-label 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 a major relapse.

        2. TOF: 5mg bid p.o.

        3. MTX: 15mg qw p.o.

        4. Treatment shift: if the TAK patients in the TOF group failed to reach clinical remission
           at the end of the 24th week, they would be shifted to MTX 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

Methotrexate Tablets

Study Arms / Comparison Groups

 methotrexate
Description:  This group of 38 TAK cases are prescribed with methotrexate tablets (Dose: 15.0 mg. qw. p.o.) 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

Drug

Estimated Enrollment

130

Start Date

March 1, 2020

Completion Date

December 31, 2023

Primary Completion Date

December 31, 2022

Eligibility Criteria

        Inclusion Criteria:

          1. age≥14 years;

          2. active status: Kerr score≥ 2;

          3. mild and moderate:

               1. Blood pressure (maximum) < 180/110mmHg;

               2. 1-2 branches with the stenotic rate < 70% involved;

               3. mildly ischemic manifestation relative to activity but relieve after rest;

               4. no or low degree of organ insufficiency: NYHF I~II; eGFR (MRDR) ≥ 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, +86-15221160538, [email protected]

Location Countries

China

Location Countries

China

Administrative Informations


NCT ID

NCT04299971

Organization ID

TACTIC-MM


Responsible Party

Sponsor

Study Sponsor

Shanghai Zhongshan Hospital


Study Sponsor

Lindi Jiang, PhD, Study Chair, Fudan University


Verification Date

March 2020