Tocilizumab for the Treatment of Familial Mediterranean Fever

• Register: EUCTR
• Last refreshed on: 5 July 2021
• Main ID: EUCTR2016-004505-13-DE
• Date of registration: 21/08/2017
• Prospective Registration: Yes
• Primary sponsor: University Hospital Tuebingen
• Public title: Tocilizumab for the Treatment of Familial Mediterranean Fever
• Scientific title: Tocilizumab for the Treatment of Familial Mediterranean Fever – A randomized, doubleblind, phase II proof of concept study-TOFFIFE - Tocilizumab for the Treatment of Familial Mediterranean Fever
• Date of first enrolment: 27/11/2017
• Target sample size: 30
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004505-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: Proof-of-Concept; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany

Contacts

• Name: Department of Internal Medicine II
• Affiliation: University Hospital Tuebingen

• Name: Department of Internal Medicine II
• Affiliation: University Hospital Tuebingen

Key inclusion & exclusion criteria

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

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 30
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 stu

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Adult patients with Familial Mediterranean Fever, who have active disease
MedDRA version: 20.0 Level: PT Classification code 10016207 Term: Familial mediterranean fever System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Trade Name: RoActemra® 20mg/ml Konzentrat
Tocilizumab
Pharmaceutical Form:
INN or Proposed INN: INN-Tocilizumab
CAS Number: 375823-41-9
Other descriptive name: TOCILIZUMAB
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 8-
Pharmaceutical form of the placebo: Infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Main Objective: 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

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

Secondary Objective: - 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

Timepoint(s) of evaluation of this end point: at week 16

Secondary Outcome(s)

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

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

Secondary ID(s)

TOFFIFE

Source(s) of Monetary Support

University Hospital Tuebingen

Roche

Ethics review

Status: Approved
Approval date: 27/11/2017
Contact: