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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Heidelberg AöR

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

5 Oct 2022 → ongoing

Decision date (initial)

2024-01-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-510376-31-00

EudraCT number

2016-004786-80

ClinicalTrials.gov

NCT03925194

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate efficacy of treatment with anakinra in
subjects with cystic fibrosis (CF) by means of lung
clearance index (LCI) in adults and in addition in
adolescents if effective in adults.

Secondary objectives 1

1. To evaluate safety and tolerability of treatment with anakinra as well as to investigate further effects of anakinra on lung function and quality of life (QOL) in subjects with CF.

Conditions and MedDRA coding

Cystic fibrosis

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Age ≥ 18 years (1st cohort). If justified by interim analysis, 18 > age ≥ 12 years (2nd cohort),
2. Informed consent of the patient (if applicable) and/or all legal guardians,
3. 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),
4. 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,
5. FEV1 ≥ 50 % pred. at screening,
6. LCI2.5 ≥ 7.05 at screening,
7. Ability to perform reproducible multiple breath washout and spirometry,
8. Oxyhaemoglobin saturation of ≥ 90% on room air at screening,
9. 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),
10. 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,
11. Adequate liver function assessed on the basis of: GGT, ASAT, and ALAT <3 x upper limit of normal (ULN),
12. Adequate blood clotting assessed on the basis of: aPTT <39 sec., INR <1.2,
13. 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),
14. 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)),
15. Use of adequate contraception in sexually active female subjects (sexual abstinence, hormonal contraceptives or intrauterine device).

Exclusion criteria 17

1. Expected non-compliance, i.e. inability or unwillingness to comply with study-specific procedures,
2. Known allergy to anakinra or any ingredient of the pharmaceutical formulation of Kineret®,
3. 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,
4. GFR <60ml/min/1.73qm,
5. History of tuberculosis or repeated detection of non-tuberculous mycobacteria from airway samples in the last 12 months before start of each treatment period,
6. History of detection of Burkholderia cenocepacia species in the last 12 months before start of each treatment period,
7. 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,
8. 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,
9. 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),
10. 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,
11. Participation in another interventional trial within the last 30 days prior to screening,
12. Current oral corticosteroid use,
13. Current oxygen supplementation,
14. Current treatment with etanercept,
15. Medical history of lung transplantation,
16. Pregnant or nursing females (females of childbearing potential must have a negative pregnancy test at screening),
17. Known hypersensitivity to hypertonic saline (used for induction of sputum).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Absolute pre-post change of the lung clearance index (LCI).

Secondary endpoints 8

1. Evaluation of the safety and tolerability of the 28- days-treatment with anakinra by means of: o Physical examination o (Serious) adverse events o Laboratory safety parameters (clinical chemistry, hematology, clotting)
2. Investigation of the effects of anakinra on lung function by means of absolute change in percentage points predicted forced expiratory volume in 1 second (FEV1 and FEV1 % pred).
3. Evaluation of the impact of anakinra on the quality-of-life (QoL) in the considered population by means of the Cystic Fibrosis Questionnaire – Revised (CFQ-R, German version).
4. Investigation of the effects of anakinra on lung function by means of absolute change in forced expiratory flow75 in liters/second and percent predicted (FEF75 and FEF75 % pred) and forced vital capacity in liter and percent predicted (FVC and FVC % pred).
5. Assessment of the influence of anakinra on lung structure and perfusion determined by chest MRI (optional sub-study).
6. Assessment of the influence of anakinra on airway inflammation by means of the following parameters: o Characterization of immune cells (absolute cell counts) in sputum samples o Inflammatory markers in sputum samples.
7. Assessment of the influence of anakinra on the bronchial infection status by means of sputum microbiology.
8. Assessment of sputum rheology

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Heidelberg AöR

Sponsor organisation

Universitaetsklinikum Heidelberg AöR

Address

Im Neuenheimer Feld 672, Neuenheim Neuenheim

City

Heidelberg

Postcode

69120

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

PD Dr. med. Olaf Sommerburg

Public contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

PD Dr. med. Olaf Sommerburg

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

2 submissions — initial application plus substantial / non-substantial modifications