A Study to Evaluate the Efficacy and Safety of CHF10196 Tablets (Florensocatib) Compared With Placebo in Male and Female Participants 12 to 85 Years of Age With Bronchiectasis

A Phase III, Randomised, Double-blind, Two-arm Study to Investigate the Efficacy and Safety of Treatment With CHF10196 Tablets (Florensocatib) Compared With Placebo for up to 78 Weeks, Followed by an Open-label Extension, in Male and Female Participants 12 to 85 Years of Age With Bronchiectasis

This study aims to find out whether the tablet CHF10196 is safe and effective for people with non-cystic fibrosis bronchiectasis, a long-term lung disease that causes widened airways, mucus buildup, infections, and flare ups of symptoms. The main goal is to see whether CHF10196 can reduce the number of lung flareups each year compared with placebo. The study will also assess whether it can improve lung function, quality of life, and overall safety.

The study has two phases. In the first phase, participants receive either CHF10196 tablets or placebo without knowing which one they are taking. In the second phase, all participants receive CHF10196 so its long-term safety can be further studied. Adults aged 18 to 85 years and adolescents aged 12 to under 18 years can take part, while continuing their usual stable bronchiectasis treatment.

Up to about 2.5 years of participation are planned. Around 904 participants will be enrolled, with regular clinic visits and phone check ins. In the first phase, participants take either CHF10196 or inactive tablets once daily; in the second phase, everyone takes CHF10196 once daily. Temporary treatment interruptions are allowed if needed, and participants who stop treatment early may still continue study visits, depending on the study phase.

Inclusion Criteria for Main Study:

1. Signed and dated informed consent obtained prior to any study-related procedure; Adolescents: Written informed consent obtained from the parent(s)/legally authorised representative(s) (according to the local regulation) and written or verbal assent by the participant (when appropriate), obtained prior to any study-related procedures;

2. Adults: Male or female participant ≥18 and ≤85 years of age; Adolescents: Male or female participant ≥12 and <18 years of age;

3. Adults: BMI (body mass index) >18.5 kg/m² at screening; Adolescents: Body weight >30 kg at screening;

4. Clinical history consistent with bronchiectasis (cough, chronic sputum production, and/or recurrent respiratory infections) confirmed by centralised reading of a chest CT, not more than 5 years old demonstrating bronchiectasis affecting 1 or more lobes; Note: If no recent chest CT is available, or if the records/report is not available, a new CT chest will be performed during the screening period;

5. A history of at least 2 pulmonary exacerbations treated with antibiotics, or 1 pulmonary exacerbation treated with antibiotics with additional risk factors (SGRQ Symptoms score at screening >40) in the past 12 months prior to screening; Adolescents: A history of at least 1 pulmonary exacerbation in the 12 months prior to screening;

6. Post-bronchodilator FEV1 ≥30% of the predicted value, calculated using the Global Lung Function Initiative 2012 reference equations; Note: in case post-bronchodilator spirometry quality is not judged satisfactory as per ATS/ERS acceptability and usability criteria*, it may be re-checked on the same day (after a sufficient period of rest) or once before randomisation if it cannot be performed on the same day;

7. Participants may either be:

   • on stable background therapy for at least 3 months prior to screening;
   • not on background therapy at screening and not planning to start background therapy;

8. Able to provide sputum at screening (adults only);

9. Cooperative attitude and ability to read/write, perform all study-related procedures, and use electronic device, ability to understand the risks involved;

10. If female, the participant must be of non-childbearing potential, surgically sterile, postmenopausal, or she and her partner must use adequate methods of contraception** during the study and for 90 days after the last dose of study intervention. Participants must not donate eggs during the study and for 90 days after the last dose of IMP (investigational medicinal product); Note: In case of hormonal contraception, an additional non-hormonal method (barrier method, preferably male condom) is required. The status of adolescent females being not of childbearing potential at screening will be monitored at each further visit (except the Follow-up visit);

11. If male, the participant and his partner must agree to use adequate methods of contraception** during the study and for at least 90 days after the last dose of study intervention.

Inclusion Criteria for OLE (Extension) Study:

1. Participant's written informed consent for the OLE Phase obtained prior to any study-related procedures of the OLE Phase; Adolescents: Written informed consent for the OLE Phase obtained from the parent(s)/legal representative(s) (according to the local regulation) and written or verbal assent by the participant (when appropriate), obtained prior to any study-related procedures of the OLE Phase;
2. Participants (adults or adolescents) who completed the treatment period of the Main Phase
3. Participants with study intervention compliance ≥70% during the Main Phase
4. If female, the participant must be of non-childbearing potential, surgically sterile, postmenopausal, or she and her partner must use adequate methods of contraception* during the study and for 90 days after the last dose of study intervention. Participants must not donate eggs during the study and for 90 days after the last dose of study intervention; Note: In case of hormonal contraception, an additional non-hormonal method (barrier method, preferably male condom) is required. The status of adolescent females being not of childbearing potential at screening will be monitored at each further visit (except the Follow-up visit);
5. If male, the participant and his partner must agree to use adequate methods of contraception* during the study and for at least 90 days after the last dose of study intervention. Participants must not donate sperm during the study and for 90 days after the last dose of study intervention.

Exclusion Criteria for Main Study:

1. Participants who have experienced any degree of pulmonary exacerbation or are experiencing a pulmonary exacerbation within 4 weeks prior to screening or during the screening period; Note: Participants can be rescreened only after recovery and 4 weeks after the last dose of antibiotic treatment;

2. Current diagnosis of CF (cystic fibrosis) as determined by Investigator;

3. Known history of invasive opportunistic infections (such as but not limited to histoplasmosis, pneumocystosis, or aspergillosis) and/or abnormally frequent or prolonged infections suggesting an immunocompromised status judged incompatible with the introduction of a DPP1 inhibitor by the Investigator;

4. Diagnosis of A1ATD -Alpha-1-antitrypsin deficiency- (defined as A1AT serum level <110 mg/dL) currently being treated with augmentation therapy; Note: A prior test result of A1AT serum level to confirm the diagnosis will be acceptable;

5. Participants with a diagnosis of non-tuberculosis mycobacteria, pulmonary infection or TB (tuberculosis), or allergic bronchopulmonary aspergillosis currently being treated or requiring treatment as determined by the Investigator;

6. Participants receiving a systemic immunosuppressive therapy for the treatment of an autoimmune disease;

7. History of malignancy in the past 5 years (excluding cured basal cell carcinoma of the skin, carcinoma in situ and papillary thyroid carcinoma) or treatment of malignancy in the past 5 years;

8. Have significant haemoptysis (≥300 mL or requiring blood transfusion) within 4 weeks prior to screening or during the screening period;

9. Participants with a severe concomitant disease or disorder that, in the opinion of the Investigator, may put the participant at risk by participating in the study, or interfere with the participant's treatment, assessment, or influence the results of the study, or have compliance issues with the study. Examples include, but are not limited to, cardiovascular conditions (e.g. NYHA Class III or IV cardiac failure), pulmonary conditions (e.g. severe pulmonary fibrosis or lung transplantation), infectious diseases (e.g. severe COVID-19 infection), gastrointestinal conditions, hepatobiliary conditions (e.g. Child-Pugh class B or C), severe renal conditions (e.g. severe nephrotic syndrome), neurological conditions (e.g. demyelinating diseases), musculoskeletal, endocrine, metabolic or psychiatric conditions;

10. Have elevated liver function test results (ALT or AST >2x ULN) or have a bilirubin >1.5x ULN at screening (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%);

11. Have an abnormal renal function test result (eGFR <60 mL/min by CKD-EPI formula for adults or CKiD-U25 formula for adolescents) at screening

12. Participants with an absolute blood neutrophil count <1000/ mm3 at screening;

13. Participants with a history of alcohol or drug abuse within 6 months prior to screening as per DSM V criteria;

14. Clinically significant abnormal laboratory values at screening that, in the opinion of the Investigator, may put the participant at risk by participating in the study, or interfere with the participant's treatment or assessment, or influence the results of the study;

15. Blood donation or blood loss (≥450 mL) less than 2 months prior to screening;

16. Participants who currently smoke tobacco or who stopped smoking within 3 months prior to screening or who are not willing to abstain from smoking for the duration of the trial; Note: any form of smoking (cigarettes, e-cigarettes, vaping, cannabis) is forbidden during the whole trial

17. Introduction of new chronic treatment for NCFBE - Non-cystic fibrosis bronchiectasis- (oral or inhaled antibiotics, ICS (inhaled corticosteroids), or low-dose oral steroids*), if started <3 months prior to screening or during the screening period

    *Low-dose oral steroids defined as <10 mg/day of prednisone or equivalent

18. Use of any immunomodulatory agents (including but not limited to: bortezomib, ixazomib, thalidomide, cyclophosphamide, mycophenolate, Janus kinase inhibitors, IFN-γ, and azathioprine) or chronic treatment with high-dose oral steroids* within 4 weeks prior to screening or during the screening period

    *High-dose oral steroids defined as ≥10 mg/day of prednisone or equivalent

19. Use of strong CYP3A inducers (including but not limited to: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampicin) within 4 weeks prior to screening or during the screening period

20. Previous treatment with another DPP1 (Dipeptidyl peptidase 1) inhibitor within 6 months before screening or during the screening period Note: participants who were randomised and only received placebo in studies with DPP1 inhibitor are allowed;

21. Participant expected to take prohibited concomitant medications during the study

22. Received any live attenuated vaccine within 4 weeks prior to randomisation Note: Recent administration of a live vaccine should be checked at screening. If a live vaccine has been administered, the participant should wait for 4 weeks prior to being randomised;

23. Participants with medical conditions associated with periodontal disease (to be evaluated by a periodontist or dentist), defined as any tooth that can potentially cause pain or infection as noted in the oral exam unless they are corrected before randomisation visit (e.g. pulp necrosis); severe periodontal disease defined as having pocket depth measurements ≥6 mm on ≥2 teeth; Class 3 mobility or Class 3 furcation involvement; or scheduled tooth extraction during the study period;

24. Participants with medical conditions known to be associated with the onset of non-hereditary palmoplantar keratosis should be carefully evaluated by the Investigator. The presence, severity, and clinical significance of such conditions must be assessed to determine their relevance to study eligibility. Examples include hypothyroidism, myxoedema, chronic lymphoedema, acrocyanosis, livedo reticularis, psoriasis, lichen planus, reactive arthritis (Reiter's disease/keratoderma blennorrhagicum), pityriasis rubra pilaris, atopic dermatitis, chronic hand or contact dermatitis, chronic dermatophytosis, chloracne, extensive verruca vulgaris, and keratoderma climactericum;

25. Medications that may cause palmoplantar keratoderma (including, but not limited to, BRAF inhibitors, MEK inhibitors, selected tyrosine kinase inhibitors, systemic retinoids, and capecitabine) within 4 weeks prior to randomisation

26. Established diagnosis of hepatitis B or hepatitis C infection. Participants who have gained immunity for HBV infection after vaccination are eligible (HBsAg negative, HBsAb positive and HBcAb negative). Participants with positive HBcAb are eligible only if HBV DNA level is undetectable. Participants positive for HCV antibody are eligible only if HCV RNA is negative;

27. Known HIV infection or positive serology test at screening;

28. Known intolerance and/or hypersensitivity to DPP1 inhibitors or any of the excipients contained in the formulation used in the trial. A history of discontinuation of DPP1 inhibitors due to an adverse drug reaction is exclusionary;

29. Clinical diagnosis of Papillon-Lefèvre syndrome;

30. Abnormal and clinically significant 12-lead ECG at screening or prior to randomisation that results in an active medical problem, which may impact the safety of the participant, per the Investigator's judgement. Male participants with QTcF >450 ms and female participants with QTcF >470 ms cannot be enrolled (not applicable for participants with permanent atrial fibrillation and for participants with pacemakers). For participants aged 12 to <18 years, QTcF values should be interpreted using age-appropriate normative reference ranges;

31. Participation in other investigational trial: participants who have received an investigational drug within 1 month or 5 half-lives of the previous administered product (whichever is longer) prior to screening, or participants who have been previously randomised in the present trial, or participants who are currently participating in another clinical trial;

32. For females only (adult or adolescent): pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive serum β-hCG laboratory test. Both serum and urine pregnancy tests are to be performed at screening, and a urine pregnancy test is to be performed prior to randomisation;

33. Participants legally incapacitated or participants accommodated in an establishment as a result of an official or judicial order.

Exclusion Criteria for OLE (Extension) Study:

1. Pregnant or lactating woman;
2. ADRs*: participants who experienced an ADR (defined as an AE assessed by the Investigator as possibly related to the IMP) during the Main Phase should not be enrolled in the OLE Phase unless the Investigator considers that the AE would not prevent them from safely and effectively participating in the OLE Phase;
3. Ongoing SAEs*: participants with ongoing SAEs at the time of the last visit of the Main Phase should not be enrolled in the OLE Phase unless the Investigator considers that the ongoing SAE would not prevent them from safely and effectively participating in the OLE Phase;
4. Changes in medical history: any clinically significant changes in participant's medical history, physical examination/vital signs/laboratory analysis; concomitant therapies, documented in the Main Phase or any newly identified disease or condition that might, in the judgement of the Investigator, place the participant at undue risk;
5. Any use of prohibited medications during the Main Phase that requires to be prolonged during the OLE Phase.