A Phase 2 interventional study of Tocilizumab Infusion RoAcemtra (EU) and 0.9% physiological saline in Familial Mediterranean Fever, sponsored by University Hospital Tuebingen. Completed at 3 sites in Germany. Open to participants aged 18 Years to 64 Years. Per ClinicalTrials.gov, last updated 2020-11-18.
Sponsored by University Hospital Tuebingen · Phase 2, Interventional, and Treatment
Adult patients with Familial Mediterranean Fever, who have active disease
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.
Inclusion Criteria:
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
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:
Exclusions Related to Prior or Concomitant Therapy
Exclusions Related to General Safety
Laboratory Exclusions (at Screening)
Tocilizumab Infusion RoAcemtra (EU) or Actemra (Rest of the world)
Drug: Tocilizumab Infusion RoAcemtra (EU)
0,9% physiological Saline
Drug: Tocilizumab Infusion RoAcemtra (EU) · Drug: 0.9% physiological saline
Experimental arm's patients will obtain TCZ intravenously once every 4 weeks for 28 weeks
Also known as: Actemra
Experimental arm's patients will obtain saline intravenously once every 4 weeks for 16 weeks. If necessary, patients will get "rescue medication" after week 16 to week 28.
Efficacy: measured change of Physician's Global Assessment of disease activity (PGA)
Efficacy: measured by Physician's Global Assessment of disease activity (PGA) will be assessed at every visit The PGA will be based on a 5 point-scale (from 0 to 4): 0=none (no) disease associated clinical signs and symptoms\* 1. minimal disease associated clinical signs and symptoms\* 2. mild disease associated clinical signs and symptoms\* 3. moderate disease associated clinical signs and symptoms\* 4. severe disease associated clinical signs and symptoms\* \*sign and symptoms for evaluation of PGA: chest pain, abdominal pain, arthralgia, arthritis, skin rash, fever (body temperature ≥ 38.0°C). Patient are asked to fill out a patient's diary to help the physician to judge the PGA primary endpoint will be the number of patients achieving an adequate response to treatment at week 16, defined as: PGA ≤ 2 + normalized ESR or CRP (the one that led to inclusion must be normalized) + normalized SAA
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events-Determination of Erytthro Sedimentation Rate (ESR)
To evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). Clinical laboratory testing for all study-relevant evaluations will be performed at all visits. Laboratory testing has to include: • ESR \[mm after 1hour\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
serological remission
To evaluate the proportion of patients with the serological remission at week 16 + 28 (defined as CRP \< 0.5 mg/dl)
Time frame: at week 16, 28
SAA level
To evaluate the proportion of patients with normalized SAA level at week 16 + 28 (defined as SAA \< 10mg/l)
Time frame: at week 16 + 28
Incidence of Treatment-Emergent Adverse Events -Determination of the C-reactive protein
Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). CRP \[mg/L\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of the blood cell count
Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). complete blood cell count with differential \[cells/µl\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of serum parameters (Creatinine)
to evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). serum chemistry function tests : Creatinine \[mg/dl\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of renal parameters (Uric Acid)
to evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). renal function tests : Uric Acid \[mg/dl\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of serum and renal parameters (Glomerular Filtration Rate)
to evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). renal function tests : GFR \[ml/min\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of liver parameters (Gamma Glutamyltransferase (GGT))
Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). GGT\[IU/L\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of liver parameters ( Alanine- (ALT) -Aminotransferase)
Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). ALT \[IU/L\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of liver parameters ( Alanine-Aminotransferase (AST))
Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). AST\[IU/L\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of liver parameters (Biliribun)
to evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). Bilirubin \[mg/dl\]
Time frame: at week -4,0,4,8,12,16,20,24,28,32
Plan to share: No
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University Hospital Tuebingen