Tocilizumab for the Treatment of Familial Mediterranean Fever

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Brief Title

Tocilizumab for the Treatment of Familial Mediterranean Fever

Official Title

Tocilizumab for the Treatment of Familial Mediterranean Fever - A Randomized, Doubleblind, Phase II Proof of Concept Study

Brief Summary

      Adult patients with Familial Mediterranean Fever, who have active disease
    

Detailed Description

      FMF is a rare disease, which permanently affects daily life of the patients with severe pain
      and the risk of developing a life threatening amyloidosis. Today there are only very limited
      treatment options and an ongoing highly unmet medical need for improved treatment strategies.
      This study will be the first randomized, controlled trial to assess the benefit as well as
      the safety profile of IL6 receptor inhibition wirth TCZ in patients with FMF. Elevated tissue
      and serum levels of IL-6 have been implicated in the pathogenesis of FMF. FMF attacks are
      painfull during the period of the attack but are not life- or organthreatening and usually
      can be handeled by nonsteroidal and antipyretic treatment. Amyloidos is a longtime
      complication that appears after several years of uncontrolled disease. Placebo control
      trials' data are characterized as having greater ability to distinguish between effective and
      ineffective treatments (that is, greater assay sensitivity). The concerns about placebo use
      should revolve around the issue of risk to participants, rather than around denial of
      treatment, and that in the absence of a significant risk of harm, placebo treatment is
      acceptable. In general, it is easier to achieve statistical significance in
      placebo-controlled trials, where effects tend to be larger, such that smaller numbers of
      participants need to be exposed to the investigational medication (and research costs are
      lower.) This is especially important in rare diseases like FMF. If an active control was
      itself never evaluated in a placebo-controlled trial, using it in an equivalency study, begs
      the question of its efficacy. This is the case for Canakinumab as a potential active
      comparator in FMF. No randomized controlled trial is published for this indication by now.
      Therefore, a placebo controlled study over a period of 16 weeks seems to be justifiable
      without exposing our patients to risk of serious or irreversible harm. NSAR and antipyretic
      treatment, as a rescue therapy for attacks, is possible throughout the study. In addition,
      all patients with uncontrolled active disease despite NSAR or paracetamol will drop out and
      will be treated with escape therapy, especially Canakinumab. Based on the available safety
      data in the RA program, the adverse effects of TCZ have been shown to be manageable (e.g.
      cytopenia, liver encyme elevation), reversible and usually not treatment limiting . The
      safety profile and tolerability of TCZ are expected to be similar or even better in patients
      with FMF than in patients with rheumatoid arthritis or giant cell arteritis, as the cohort of
      FMF patients is, in general, younger and shows less concomitant diaseases. Overall, the
      benefit-risk ratio of FMF patients to be treated with TCZ is judged positive.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Efficacy: measured change of Physician's Global Assessment of disease activity (PGA)

Secondary Outcome

 Incidence of Treatment-Emergent Adverse Events-Determination of Erytthro Sedimentation Rate (ESR)

Condition

Familial Mediterranean Fever

Intervention

Tocilizumab Infusion RoAcemtra (EU)

Study Arms / Comparison Groups

 Tocilizumab
Description:  Tocilizumab Infusion RoAcemtra (EU) or Actemra (Rest of the world)

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

30

Start Date

April 23, 2018

Completion Date

October 30, 2020

Primary Completion Date

October 30, 2020

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years and written informed consent

          -  FMF according to the Tel Hashomer Criteria; with at least one heterozygous or
             homozygous mutation of the MEFV gene

          -  Inadequate response or intolerance to colchicine (inadequate response/intolerance:

        disease activity despite colchicine with at least 2 x 0.5 mg/day or intolerance to
        colchicine)

          -  Attack during the last 12 weeks, defined as episodes of fever and/or pericarditis
             and/or serositis and/or testis involvement and/or arthritis and/or erysipelas-like
             rash and

               -  CRP > 0.5 mg/dl and/or ESR > 20mm/h and/or SAA > 10mg/dl

               -  PGA >2

          -  Understand and voluntarily sign an informed consent document prior to any study
             related assessments/procedures.

          -  Ability to adhere to the study visit schedule and other protocol requirements.

          -  Females of childbearing potential (FCBP*) must agree to utilize two reliable forms of
             contraception simultaneously from heterosexual contact for at least 28 days before
             starting study drug, while participating in the study (including dose interruptions),
             and for 6 months after study treatment discontinuation and must agree to regular
             pregnancy testing during this timeframe to abstain from breastfeeding during study
             participation and 6 months after study drug discontinuation.

          -  Males must agree to use a latex condom during any sexual contact with FCBP while
             participating in the study and for 6 months following discontinuation from this study,
             even if he has undergone a successful vasectomy to refrain from donating semen or
             sperm while on Tocilizumab/Placebo and 6 months after discontinuation from this study
             treatment.

          -  All subjects must agree to refrain from donating blood while on study drug and 6
             months after discontinuation from this study treatment.

          -  All subjects must agree not to share medication.

        A female of childbearing potential is a sexually mature woman who: 1) has not undergone a
        hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at
        least 24 consecutive months (i.e., who has had menses at any time in the preceding 24
        consecutive months).

        Exclusion Criteria:

        Subjects presenting with any of the following criteria will not be included in the trial:

          -  Patient participating simultaneously in other clinical interventional trials

          -  Major surgery within 8 weeks prior to screening or planned major surgery within 12
             months after randomization

          -  Transplanted organs (except corneal transplant performed more than 3 months prior to
             screening)

        Exclusions Related to Prior or Concomitant Therapy

          -  Previous treatment with TCZ

          -  Treatment with glucocorticosteroids >10mg/day within 1 week; prednisolone ≤ 10mg/day
             can be given on a stable dose throughout the study

          -  Analgesic medication, other than paracetamol or ibuprofen or diclofenac or colchicine,
             which can be used at a stable dose throughout the study and/or for treatment of FMF
             attacks to the maximum allowed daily dose (paracetamol: 4000mg/day, ibuprofene:
             maximum 2400mg/day, diclofenac maximum 150mg/day; colchicine 12mg/day) .

          -  Treatment with any investigational agent within 12 weeks (or 5 half-lives of the
             investigational drug, whichever is longer) of screening

          -  Treatment with Anakinra within the last 1 week prior to baseline (ptb), Canakinumab
             within the last 8 week prior to baseline

          -  Treatment with etanercept within 2 weeks; certolizumab pegol, abatacept or adalimumab
             within 6 weeks; golimumab and infliximab within 8 weeks ptb

          -  Rituximab within 24 weeks ptb

          -  Leflunomide within 12 weeks ptb (washout possible),

          -  azathioprine, cyclophosphamide within 12 weeks ptb

          -  Immunization with a live/attenuated vaccine within ≤ 4 weeks ptb

          -  Previous treatment with cell-depleting therapies, including investigational agents or
             approved therapies: anti-CD33, anti-CD52, anti-CD4, anti-CD5, anti- CD3 and anti-CD19

          -  Treatment with intravenous gamma globulin within 6 months of baseline

          -  Treatment with plasmapheresis within 6 months of baseline

          -  Any previous treatment with alkylating agents such as chlorambucil, or with total
             lymphoid irradiation

        Exclusions Related to General Safety

          -  History of severe allergic or anaphylactic reactions to human, humanized, or murine
             antibodies

          -  Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary
             (including obstructive pulmonary disease), renal, hepatic, psychiatric or
             gastrointestinal (GI) disease

          -  History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic
             ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other
             symptomatic lower GI conditions that might predispose a patient to perforations

          -  Known active current or history of recurrent bacterial, viral, fungal, mycobacterial,
             or other infections (including but not limited to tuberculosis (TB) and atypical
             mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal
             infections of the nail beds)

          -  Any major episode of infection requiring hospitalization or treatment with IV
             antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of
             screening

          -  Active TB requiring treatment within the previous 3 years; patients should be screened
             for latent TB and, if positive, treated according to local practice guidelines prior
             to initiating TCZ treatment; patients treated for TB with no recurrence within 3 years
             and patients treated for latent TB within 3 years are eligible.

          -  Primary or secondary immunodeficiency (history of or currently active)

          -  Evidence of malignant disease or malignancies diagnosed within the previous 5 years
             (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the
             cervix uteri that have been excised and cured)

          -  FCBP who are not willing to use an effective method of contraception, such as condom,
             sterilization during the study and for a minimum of 6 months after study drug therapy
             and breast-feeding females

          -  Pregnant women

          -  Males of reproductive potential who are not willing to use an effective method of
             contraception, such as condom, sterilization, or true abstinence throughout study and
             for a minimum of 6 months after study drug therapy

          -  History of alcohol, drug, or chemical abuse within 1 year prior to screening

        Laboratory Exclusions (at Screening)

          -  Serum creatinine >1.4 mg/dL in female patients and >1.6 mg/dL (in male patients

          -  ALT or AST > 2 ×ULN

          -  Total bilirubin > 2 x ULN

          -  Platelet count < 100 × 109/L

          -  Hemoglobin < 8.5 g/dL

          -  White blood cells < 3.0 ×109/L

          -  Absolute neutrophil count < 2.0 × 109/L

          -  Absolute lymphocyte count < 0.5 × 109/L

          -  Positive hepatitis B surface antigen, anti-HBc, HIV or hepatitis C antibody
      

Gender

All

Ages

18 Years - 64 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT03446209

Organization ID

TOFFIFE 1.1


Responsible Party

Sponsor

Study Sponsor

University Hospital Tuebingen


Study Sponsor

, , 


Verification Date

April 2019