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