Efficacy and Tolerance of Tocilizumab In Takayasu Arteritis

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Brief Title

Efficacy and Tolerance of Tocilizumab In Takayasu Arteritis

Official Title

Efficacy and Tolerance of First-line Treatment With Tocilizumab in Active Takayasu Arteritis French Prospective Multicenter Study

Brief Summary

      First-line tocilizumab treatment during 6 months could permit rapid steroid-tapering and
      induction of remission in Takayasu arteritis (TA).
    

Detailed Description

      Scientific/Medical Rationale Takayasu arteritis (TA) is a large-vessel vasculitis that
      affects the aorta and its primary branches and may lead to arterial segmental stenosis,
      occlusion and/or aneurism formation. The symptoms are either non specific and reflect
      systemic inflammation, or related to vascular injury and induced organ-ischemia. Even though
      many patients respond to glucocorticoids, relapses or steroid-dependence may necessitate the
      use of combination therapy. Azathioprine (2 mg/kg/day) and methotrexate (20-25 mg/week) have
      been used in patients with TA, and can induce disease remission and prevent the development
      of new arterial lesions. The addition of other immunosuppressive agents to glucocorticoids
      could be required in majority of patients. Magnetic resonance imaging constitutes an
      interesting non-invasive imaging to assess arterial changes during follow-up.

      The pathogenesis of TA includes vessel injury mediated by T-cells, natural killer cells, γδ-T
      cells and macrophages. T-cells and macrophages infiltrates contribute to granuloma and giant
      cells formation, and produce IFNγ which stimulate the production of pro-inflammatory
      cytokines. The secretion of pro-inflammatory cytokines, including TNFα and IL-6, is
      implicated in vascular inflammation and injury in TA.

      In the light of these data, several studies have reported the efficacy of TNFα inhibitors in
      TA, but only one observational study of 15 cases and a few case-reports are available. The
      investigators have reported the French multicenter experience on infliximab in TA. In this
      cohort of 15 french TA patients refractory to other immunosuppressive agents with more than
      20 mg prednisone daily, infliximab enabled a significant improvement of both clinical and
      biological features, in addition to having a steroid-sparing effect. Furthermore, early
      response was notable, since clinical, biological remission and steroid-sparing were achieved
      within 3 months in the investigators refractory TA patients.

      The importance of targeting pro-inflammatory cytokines in TA was recently raised by the
      report of the efficacy of the humanized anti-IL6 receptor antibody (tocilizumab). Likewise to
      TNF-α inhibitors, a dramatic and rapid improvement in clinical manifestations and on
      laboratory parameters was noted. This early response in even long-standing TA disease, as
      also noted in the investigators study and in previous reports, supports the use of
      cytokine-targeting therapies in TA.

      Like other immunosuppressive agents in TA, TNF-α inhibitors and tocilizumab were used mostly
      in refractory TA disease, and thus its benefits as a first-line treatment option,
      particularly with regard to their steroid-sparing effect and in prevention of relapses, could
      not be assessed.

      Recently in severe and relapsing ANCA-associated vasculitis, the use of initial biotherapy
      with rituximab was sufficient to induce remission and permit completely tapering
      glucocorticoids at 6 months, comparatively to the conventional cyclophosphamide-based
      regimen.

      Given the limited treatment options and the number of TA, a multicenter trial may be
      necessary to address the benefits of first-line tocilizumab treatment in inducing remission
      and as steroid-sparing strategy.

      Hypothesis:

      • First-line tocilizumab treatment during 6 months could permit rapid steroid-tapering and
      induction of remission in TA.

      Primary objective:

        -  Evaluation of number of good responders without prednisone after 6-months tocilizumab
           treatment

      Secondary objectives:

        -  Influence of 6-months tocilizumab treatment to induction of partial and good responders
           at 3, 6 and 12 months

        -  Influence of 6-months tocilizumab treatment to cumulative dose of steroids during 6
           months

        -  Evaluate the TA global activity associated with tocilizumab treatment, by the
           questionnaires: BVAS, PGO, Dei-Tak

        -  Evaluate the radiological response : PET and MRI at 6, 9 and 12 months

        -  Evaluate the biological response

        -  Evaluate the clinical response

        -  Evaluate the patients' quality of life associated with tocilizumab treatment, by the
           quality of life questionnaires: SF-36

        -  Determine time to recurrence during the observation period of 12 months

        -  Safety as adverse events.

      Number of subjects:

        -  The number of patient will be 15 patients with active TA, as this protocol is a
           non-comparative pilot study.

        -  A number of 15 patients was chosen, as in this rare disease the 2 most important studies
           with TNFalpha antagonists included 15 subjects. In these studies complete or partial
           response was obtained in almost 70% of patients, but concerned refractory patients. In
           concern on tocilizumab, only case reports are available and all demonstrate a
           spectacular improvement and 100% clinical, biological and radiological improvement and
           the response seem to be better than to TNFalpha antagonists. Thus, the investigators
           calculate at least 50% of response with first-line tocilizumab which could taper
           steroids at 6 months, with ± 25% precision with the number of included patients.

      Study assessments:

      • Patients will undergo a screening visit and an inclusion visit and will be assessed at
      weeks 4, 8, 12, 24, 36, 48, 60, 72.

      Duration of Treatment per subject/patient:

      • 18 months comprising 6 months treatment and 12 months follow-up

      Duration of Trial Recruitment:

        -  24 months

      Definitions of activity and treatment response:

      • Active disease is defined as the presence of activity at least in 1 of 3 domains (clinical,
      biological and /or radiological)

      Definition of activities:

        -  Clinical disease activity is defined if the patient presented one of the following
           features: (1) new onset and/or aggravation of carotodynia, pain over other large vessels
           or ischemic vascular claudication, (2) transient ischemic episodes not attributed to
           other factors, (3) new bruit or asymmetry in pulses or blood pressure, (4) systemic
           features in the absence of infection or other factors.

        -  Biological disease activity is defined by the presence of 2 of the following features:

           (1) VS>30 mm/h, (2) CRP>10 mg/l, (3) fibrinogen>3 g/l without any infection.

        -  Radiological activity is defined as the presence of one of the following features:

             1. arterial wall thickening with mural enhancement in resonance magnetic imaging, (2)
                arterial hypermetabolism on PET-scan, (3) new arterial lesions on resonance
                magnetic imaging and /or PET-scan at 3 and/ or 6 months.

                Partial responder is defined as patient with response in 2 among 3 domains, Good
                responder is defined as patient as patient with response in all 3 domains
                (clinical, radiological, biological).

                • Clinical response: (1) the absence of new clinical features and (2) stability or
                disappearance of baseline features*

                  -  Biological response: disappearance of baseline features or at least 50%
                     decrease*

                  -  Radiological response: (1) the absence of new radiological features and (2)
                     stability or disappearance of baseline features*

                       -  These as endpoint measures are not collected as Adverse Events (unless
                          they do not meet the criteria specified).

                Primary Endpoint:

                • The main endpoint will be number of good responders without prednisone after
                6-months of tocilizumab.

                Secondary Endpoints:

                The secondary endpoints will assess:

                • the number of good and partial responders at 3 , 6, 12 months,

                • influence of 6-months tocilizumab treatment to cumulative dose of steroid during
                6 months

                • TA global activity associated with tocilizumab treatment, by the questionnaires:
                BVAS, PGO, Dei-Tak;

                • the clinical response

                • the biological response;

                • the radiological response : PET and MRI at 6, 9 and 12 months;

                • patients quality of life associated with tocilizumab treatment, by the quality of
                life questionnaires: SF-36

                  -  time to recurrence during the observation period,

                  -  safety as adverse events.

                Safety:

                Monitoring standard of care for Tocilizumab treatment, as per European SmPC.
                Investigators must immediately notify the sponsor, AP-HP of serious adverse events
                (SAE) and serious and non serious adverse events of special interest (AESI).

                The clinical outcome and the results of any clinical assessments and diagnostic
                and/or laboratory investigations and any other information providing a reasonable
                analysis of the causal relationship will therefore be reported. For serious adverse
                effects the ethical committee and research investigators must be informed.

                All SAE and AESI (serious and non serious), need to be reported to Roche within 24
                hours. Categories of AESI have been identified for ACTEMRA (Tocilizumab):
                infections (including opportunistic infections), myocardial infarction/acute
                coronary syndrome, gastrointestinal perforations and related events, malignancies,
                anaphylaxis/hypersensitivity reactions, demyelinating disorders, stroke, bleeding
                events, hepatics events. The Investigators should use their clinical judgement to
                identify events falling in any of these AESI categories.

                For all AESI (serious and non serious), Guided Questionnaires will be used to
                obtain follow up information.

                Statistical analyses The aim of the descriptive analysis will be to determine the
                variation of the different parameters during the follow-up and to evaluate their
                importance. Data will be presented as means with standard deviations, medians with
                interquartiles, ranges including the missing data for continuous variables. Data
                will be presented as frequencies with percentages (95%CI) for qualitative
                variables.

                Kaplan Meier estimation will be used for the analysis of the time to occurrence of
                categorical parameters (pe different response: yes/no). The evolution of the
                different continuous variables will be analyzed with the model of ANOVA (random
                effect) and could be normalized if necessary. In case of failure, rank analyses
                will be performed. All tests will be considered as significant with p < 0.05. "

                Perspectives:

                This first study of Tocilizumab in TA could assess that fist-line tocilizumab
                induce remission and steroid-tapering. This study could ascertain the new option of
                treatment of vasculitis, as rapid induction of remission by combination therapy to
                obtain steroid-tapering and long-standing remission.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

number of good responders without prednisone after 6-months tocilizumab treatment

Secondary Outcome

 Number of good and partial responders at 3 , 6, 12 months

Condition

TAKAYASU ARTERITIS

Intervention

Tocilizumab

Study Arms / Comparison Groups

 TOCILIZUMAB MONTHLY DURING 6
Description:  intravenous injection, 8 mg/kg, monthly during 6 months

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

18

Start Date

June 10, 2014

Completion Date

February 1, 2019

Primary Completion Date

December 10, 2018

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of TA : ACR and /or Ishikawa modified Sharma criteria of TA

          -  Age of 18 years or older

          -  Willing to use an effective means of birth control throughout the study

        Exclusion Criteria:

          -  Patients immunosuppressive treatment or biologics other than steroids 4 months before

          -  Evidence of active infection (including chronic infection)

          -  HIV infected, hepatitis C infected, or a positive hepatitis B surface antigen

          -  History of any malignant neoplasm except adequately treated basal or squamous cell
             carcinoma of the skin or solid tumors treated with curative therapy and disease-free
             for at least 5 years

          -  Inability to provide informed consent

          -  Cytopenia, as defined by platelet count < 100 × 109/L (100,000/mm3), hemoglobin < 85
             g/L (8.5 g/dL; 5.3 mmol/L), absolute neutrophil count < 2.0 × 109/L (2000/mm3),
             absolute lymphocyte count < 0.5 × 109/L (500/mm3)

          -  Insufficient liver function

          -  Insufficient kidney function, as defined by a serum creatinine of more than 3 mg/dL or
             creatinine clearance of 20 ml/min or less

          -  Positive tuberculin skin test and/or positive Quantiferon

          -  Radiographic evidence suggestive of tuberculosis

          -  Contraindication to and precaution in use of Tocilizumab according to the summary
             product description

          -  Pregnancy
      

Gender

All

Ages

18 Years - 77 Years

Accepts Healthy Volunteers

No

Contacts

Olivier FAIN, , 

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT02101333

Organization ID

P130404


Responsible Party

Sponsor

Study Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

 Chugai Pharmaceutical

Study Sponsor

Olivier FAIN, Principal Investigator, médecine interne - St Antoine


Verification Date

July 2020