A phase IIa, randomized, placebo-controlled, double-blind, cross-over study to evaluate safety and efficacy of subcutaneous administration of anakinra in patients with cystic fibrosis

Prior treatment

• Immunosuppressive treatment due to organ transplantation, rheumatic or autoimmune diseases as well as treatment with Anakinra in the last 3 months before Day 1 of Period 1,
• Participation in another interventional trial within the last 30 days prior to screening,
• Current oral corticosteroid use,
• Current treatment with etanercept,
• Planned immunization with attenuated (live) vaccine(s) during the treatment with the IMP or completed immunization with attenuated (live) vaccine(s) within 4 weeks prior to the first administration of the IMP,
• History of tuberculosis or repeated detection of non-tuberculous mycobacteria from airway samples in the last 12 months before start of each treatment period,
• History of detection of Burkholderia cenocepacia species in the last 12 months before start of each treatment period,
• Acute bronchopulmonary exacerbation (defined by modified Fuchs criteria (23) (see Appendix 1), modification includes all ways of application of an antibiotic (e.g., oral, i.v., inhaled)) within 14 days prior to the screening and before start of each treatment period,

Other illness

• Medical history of lung transplantation,
• Known hypersensitivity to hypertonic saline (used for induction of sputum).
• Known allergy to anakinra or any ingredient of the pharmaceutical formulation of Kineret®,

Lab values

• GFR <60ml/min/1.73qm,
• Signs of other active infection within 14 days prior to the screening and before start of each treatment period (clinical symptoms (e.g. burning sensation while urinating, skin, wound or dental infection) and/or fever and/or deterioration of infection-specific laboratory parameters beyond changes driven by the underlying disease),

Other

• Expected non-compliance, i.e. inability or unwillingness to comply with study-specific procedures,
• Current oxygen supplementation,
• Pregnant or nursing females (females of childbearing potential must have a negative pregnancy test at screening),
• Known colonization with multi-resistant Staphylococcus aureus (MRSA) and/or 4-multiresistant gram negative (MRGN) Pseudomonas aeruginosa is only an exclusion criterion if the treating physician judges that this is an increased risk for the patient,

• Age ≥ 18 years (1st cohort). If justified by interim analysis, 18 > age ≥ 12 years (2nd cohort),
• Adequate bone marrow function assessed on the basis of: neutrophils >1.5 x 109/L, platelets >100 x 109/L, hemoglobin >9.0 g/dL,
• Adequate liver function assessed on the basis of: GGT, ASAT, and ALAT <3 x upper limit of normal (ULN),
• Adequate blood clotting assessed on the basis of: aPTT <39 sec., INR <1.2,
• Negative serology for HIV (anti-HIV 1/2 IgG/IgM and p24-Ag), HBV (people without history of HepB vaccination: anti-HBs quantitative and anti-HBc IgG/IgM must be negative; people with history of HepB vaccination: anti HBc IgG/IgM negative) and HCV (anti-HCV IgG), negative Interferon-gamma release assay (people with history of a latent infection with Mycobacterium tuberculosis (LTBI), documented adequate treatment of LTBI, and with airway samples negative for Mycobacterium tuberculosis can have a positive test result),
• Negative Beta-HCG blood/urine test in women of childbearing potential (of childbearing potential are females who have experienced menarche and are not permanently sterile or postmenopausal (postmenopausal: 12 consecutive months with no menses without an alternative medical cause)),
• Use of adequate contraception in sexually active female subjects (sexual abstinence, hormonal contraceptives or intrauterine device).
• Informed consent of the patient (if applicable) and/or all legal guardians,
• Sufficient fluency of patient and/or his/her representative in German language to comply with study-specific procedures (e.g. to complete required quality of life questionnaires),
• Confirmed diagnosis of cystic fibrosis, fulfilling at least one of the following three criteria: a. sweat chloride ≥ 60mEq/L, b. two CF causing mutations in the CFTR gene, c. alterations of transepithelial potential difference of nasal or rectal epithelia typical for CF,
• FEV1 ≥ 50 % pred. at screening,
• LCI2.5 ≥ 7.05 at screening,
• Ability to perform reproducible multiple breath washout and spirometry,
• Oxyhaemoglobin saturation of ≥ 90% on room air at screening,
• No changes in the medication for cystic fibrosis lung disease for at least 4 weeks prior to the first administration of the IMP of each treatment period (in case of medication changes in Period 1 and/or the washout phase the wash-out may be extended for up to 12 weeks in order to fulfill this criterion),