E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients with Familial Mediterranean Fever, who have active disease |
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E.1.1.1 | Medical condition in easily understood language |
Familial Mediterranean Fever |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016207 |
E.1.2 | Term | Familial mediterranean fever |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of Tocilizumab in patients with active FMF in a randomized, placebo controlled setting
Efficacy: measured by Physician’s Global Assessment of disease activity (PGA) at week 16 Primary endpoint will be the number of patients achieving an adequate response to treatment at week 16, defined as: PGA ≤ 2 + normalized ESR and/or CRP (the one that led to inclusion must be normalized) + normalized SAA |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of TCZ in subjects with FMF - To evaluate the proportion of patients achieving a Physician Global assessment of disease activity (PGA) ≤ 2 (minimal or none) at week 16 - To evaluate the proportion of patients with the serological remission at week 16 + 28 (defined as CRP < 0.5 mg/dl) - To evaluate the proportion of patients with normalized SAA level at week 16 + 28 (defined as SAA < 10mg/l) - To evaluate the possibility of reducing intake of ibuprofene, diclofenac or paracetamol - To evaluate health related quality of live assessed by FFbH, FACIT Fatigue |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age ≥ 18 years and written informed consent - FMF according to the Tel Hashomer Criteria (Appendix); with at least one heterozygous or homozygous mutation of the MEFV gene - Inadequate response 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 >0.5mg/dl and/or ESR >20mm/h and/or SAA >10mg/dl - Physician Global Assessment (PGA) >2 - Able and willing to provide written informed consent and to comply with the study protocol
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E.4 | Principal exclusion criteria |
Subjects presenting with any of the following criteria will not be included in the trial: - Age < 18 years - 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 glucocorticosteroide > 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, which can be used at a stable dose and for treatment of FMF attacks. - 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 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) - Females of childbearing 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 and females who are breastfeeding - 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
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: measured by Physician’s Global Assessment of disease activity (PGA) at week 16 Primary endpoint will be the number of patients achieving an adequate response to treatment at week 16, defined as: PGA ≤ 2 + normalized ESR and/or CRP (the one that led to inclusion must be normalized) + normalized SAA |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- To evaluate the safety of TCZ in subjects with FMF - To evaluate the proportion of patients achieving a Physician Global assessment of disease activity (PGA) ≤ 2 (minimal or none) at week 16 - To evaluate the proportion of patients with the serological remission at week 16 + 28 (defined as CRP < 0.5 mg/dl) - To evaluate the proportion of patients with normalized SAA level at week 16 + 28 (defined as SAA < 10mg/l) - To evaluate the possibility of reducing intake of ibuprofene, diclofenac or paracetamol - To evaluate health related quality of live assessed by FFbH, FACIT Fatigue |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
disease activity (PGA) ≤ 2 (minimal or none) at week 16 serological remission at week 16 + 28 proportion of patients with normalized SAA level at week 16 + 28 To evaluate the possibility of reducing intake of ibuprofene, diclofenac or paracetamol at week 16 and 28 To evaluate health related quality of live assessed by FFbH, FACIT Fatigue at week 16 and 28 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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In case of the following situations, a premature termination of the trial has to be considered: • Serious adverse drug reactions / not justifiable toxicity • Substantial changes in risk-benefit considerations • New insights from other trials • Insufficient efficacy • Insufficient recruitment rate
For further information see chapter 6.10 to 6.12 of the submitted protocol |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |