Evaluation of Anakinra Efficacy and Safety in Cystic Fibrosis: A Phase IIa Randomized, Placebo-Controlled, Double-Blind, Cross-Over Study
- Trial ID
- 2023-510376-31-00
- Protocol
- ANAKIN
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase IIa, randomized, placebo-controlled, double-blind, cross-over study is to evaluate the **efficacy** of treatment with anakinra in patients with **cystic fibrosis** (CF). This will be assessed by measuring the lung clearance index (LCI) in adults, and potentially in adolescents if the treatment proves effective in adults. The clinical relevance of this objective lies in the potential improvement of pulmonary function, which is a critical concern in the management of cystic fibrosis.
Secondary objectives include:
- Evaluating the **safety** and tolerability of anakinra treatment.
- Investigating further effects of anakinra on lung function.
- Assessing the impact of anakinra on the quality of life (QOL) in subjects with cystic fibrosis.
Participants
The clinical trial involves participants diagnosed with **cystic fibrosis**, with the primary objective of evaluating the efficacy of treatment with anakinra. The study population includes both male and female subjects, with an age range starting from 18 years in the first cohort, and potentially extending to adolescents aged 12 years and older in a second cohort, contingent upon interim analysis results. Participants are required to have adequate bone marrow, liver function, and blood clotting capabilities, as well as a negative serology for HIV, HBV, and HCV. Women of childbearing potential must have a negative Beta-HCG test and use adequate contraception. The trial includes individuals who are fluent in German to ensure compliance with study-specific procedures. Participants must have a confirmed diagnosis of cystic fibrosis, with specific criteria such as sweat chloride levels, CFTR gene mutations, or transepithelial potential difference alterations. The study requires a minimum FEV1 of 50% predicted and an LCI2.5 of at least 7.05 at screening. Participants must maintain stable medication for cystic fibrosis lung disease for at least four weeks prior to the trial. The sponsor has not provided the total number of participants involved in the study.
Plans and Procedures
The clinical trial is a **phase IIa**, randomized, placebo-controlled, double-blind, cross-over study designed to evaluate the safety and efficacy of subcutaneous administration of **anakinra** in patients with **cystic fibrosis**. The primary objective is to assess the efficacy of anakinra treatment by measuring the lung clearance index (LCI) in adults, with potential extension to adolescents if results are favorable. The trial is expected to conclude by July 31, 2026, with recruitment having commenced on June 28, 2022.
Participants will be randomly assigned to receive either anakinra or a placebo, with the study employing a double-blind design to ensure that neither the participants nor the investigators are aware of the treatment allocations. The trial will involve a cross-over component, allowing participants to receive both the active treatment and placebo at different stages, separated by a washout period. The maximum treatment period for each participant is four weeks, with a total maximum dose of 2800 mg of anakinra administered via subcutaneous injection.
The study will include several visits, beginning with a screening visit to confirm eligibility based on criteria such as age, adequate organ function, and confirmed diagnosis of cystic fibrosis. Participants must be at least 18 years old, with the possibility of including those aged 12 to 18 if interim analysis justifies it. Follow-up visits will occur throughout the treatment period to monitor safety and efficacy, including assessments of lung function, quality of life, and potential adverse events. The end-of-study visit will evaluate the overall impact of the treatment and collect final data.
Participant involvement is expected to last for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring informed consent is obtained from all participants or their legal guardians, and maintaining confidentiality and safety throughout the study.
Treatment
The clinical trial involves the administration of **anakinra**, a recombinant human interleukin-1 receptor antagonist, formulated as a **solution for injection** in a pre-filled syringe. The pharmaceutical form is specified as a solution for injection, with each syringe containing 100 mg of anakinra in 0.67 ml. The route of administration is **subcutaneous injection**, and the dosing regimen involves a maximum daily dose of 100 mg. The total maximum dose over the treatment period is 2800 mg, with the treatment period extending up to 4 weeks. The product is manufactured by Swedish Orphan Biovitrum AB (Publ) and is identified by the marketing authorization number EU/1/02/203/006.
The study also includes a **placebo** control, referred to as Kineret Placebo. The placebo is designed to match the experimental treatment in appearance and administration method, ensuring the study remains double-blind. The placebo is administered via subcutaneous injection, similar to the active treatment, to maintain consistency in the trial protocol. The placebo is utilized to evaluate the efficacy and safety of anakinra in comparison to a non-active treatment, providing a baseline for assessing the therapeutic effects of the active drug.
Efficacy
The efficacy of the treatment with **anakinra** in patients with cystic fibrosis will be assessed primarily through the absolute pre-post change of the lung clearance index (LCI). This parameter serves as the primary endpoint for evaluating the treatment's effectiveness. Secondary endpoints include the evaluation of safety and tolerability of the 28-day treatment with anakinra, assessed through physical examinations, monitoring of (serious) adverse events, and laboratory safety parameters such as clinical chemistry, hematology, and clotting. Additionally, the effects of anakinra on lung function will be investigated by measuring the absolute change in percentage points predicted forced expiratory volume in 1 second (FEV1 and FEV1 % pred), as well as forced expiratory flow75 (FEF75 and FEF75 % pred) and forced vital capacity (FVC and FVC % pred).
The impact of anakinra on the quality of life in the study population will be evaluated using the Cystic Fibrosis Questionnaire – Revised (CFQ-R, German version). Further assessments include the influence of anakinra on lung structure and perfusion via chest MRI, airway inflammation through immune cell characterization and inflammatory markers in sputum samples, bronchial infection status via sputum microbiology, and sputum rheology. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the overall effectiveness of the treatment regimen.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years (1st cohort). If justified by interim analysis, 18 > age ≥ 12 years (2nd cohort),
- 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),
- 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).
Exclusion Criteria
- Expected non-compliance, i.e. inability or unwillingness to comply with study-specific procedures,
- Known allergy to anakinra or any ingredient of the pharmaceutical formulation of Kineret®,
- 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,
- GFR <60ml/min/1.73qm,
- 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,
- 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,
- 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,
- 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),
- 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 oxygen supplementation,
- Current treatment with etanercept,
- Medical history of lung transplantation,
- Pregnant or nursing females (females of childbearing potential must have a negative pregnancy test at screening),
- Known hypersensitivity to hypertonic saline (used for induction of sputum).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 28 Jun 2022 | 60 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Kineret Placebo | Placebo | N/A | — | — | — | N/A |
Kineret 100 mg/0.67 ml solution for injection in pre-filled syringe. | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 100 | 4 | PRD1778560 |