| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Cystic Fibrosis Bronchiectasis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Cystic Fibrosis Bronchiectasis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10083611 |
| E.1.2 | Term | Non-cystic fibrosis bronchiectasis |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of brensocatib at 10 mg and 25 mg compared with placebo on the rate of pulmonary exacerbations (PEs) over the 52-week treatment period |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of brensocatib compared with placebo on the time to first PE over the 52-week treatment period
2. To evaluate effect of brensocatib compared with placebo on the proportion of subjects who are exacerbation free over the 52-week treatment period
3. To evaluate the effect of brensocatib compared with placebo on lung function
4. To evaluate the effect of brensocatib compared with placebo on the rate of severe PEs over the 52-week treatment period
5. To evaluate the effect of brensocatib compared with placebo on quality of life, as assessed by the Quality of Life Questionnaire – Bronchiectasis (QOL-B) Respiratory Symptoms Domain Score over the 52-week treatment period
6. To assess the safety and tolerability of brensocatib compared with placebo over the 52-week treatment period |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
This study will also comprise a pharmacokinetic/pharmacodynamic (PK/PD) sub-study and a computed tomography (CT) scan sub-study.
The PK/PD sub-study will be conducted in a select number of sites. Subjects who agree will undergo sparse PK and PD sampling. Approximately 300 subjects will be included in the PK/PD sub-study.
A subgroup of subjects will be included in an evaluation of lung damage through CT scan at enrollment (Screening Visit) and End of Treatment (EOT-Week 52). Those subjects will have a guided inspiratory and expiratory CT scan done during the Screening Period and at the end of 12 months of treatment. Approximately 225 subjects (75 subjects per study arm) will be included in the CT Scan sub-study.
|
|
| E.3 | Principal inclusion criteria |
1. Provide their signed study informed consent to participate.
2. Male or female ≥18 years and ≤85 years of age (inclusive) at screening.
3. BMI ≥18.5 at screening.
4. Clinical history consistent with NCFBE (cough, chronic sputum production and/or recurrent respiratory infections) that is confirmed by chest CT demonstrating bronchiectasis affecting one or more lobes (confirmation may be based on prior chest CT).
a. For each subject, the most recent chest CT scan (but not older than 5 years before the Screening date) will be selected for transfer to the central reading facility for confirmation of the diagnosis of NCFBE.
b. If the CT scan cannot be read by the reviewers due to quality issues, a new CT scan will be performed.
c. In case a chest CT Scan in the last 5 years is not available, a new chest CT scan must be obtained for confirmation of the diagnosis of NCFBE by the central reading facility.
5. Postbronchodilator FEV1 at the Screening Visit ≥30% of predicted normal value, calculated using National Health and Nutrition Examination Survey reference equations and must have an absolute value ≥750 mL.
6. Current sputum producer with a history of chronic expectoration of at least 3 months in the past 12 months, and able to provide sputum sample during screening (Visit 1). If a subject is unable to produce sputum spontaneously during screening, the subject will be considered a screen failure. The subject should not undergo a sputum induction procedure during screening to meet inclusion criterion.
7. Mucopurulent or purulent sputum color assessed at the Screening Visit by color chart developed by MP Murray.
8. At least 2 pulmonary exacerbations defined by need for antibiotic prescription by a physician for the signs and symptoms of respiratory infections in the past 12 months before the Screening Visit.
9. Women must be post-menopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, or using highly effective double barrier contraception (ie, methods that in combination achieve <1% unintended pregnancy rates per year) from Day 1 to at least 90 days after the last dose. Such methods include true abstinence (refraining from heterosexual intercourse during the study); combined
(estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation and supplemented with a double barrier (preferably male condom); intrauterine devices; intrauterine hormone-releasing systems; or vasectomized partner. For women ≤45 years of childbearing potential, an additional confirmatory testing of FSH level with a threshold of >40 mIU/mL should be performed to be considered infertile.
10. Male subjects with female partners of childbearing potential must be using effective contraception from Day 1 to at least 90 days after the last dose. Acceptable methods include true abstinence (refraining from intercourse during the study), combined (estrogen and progestogen-containing) or progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems. |
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| E.4 | Principal exclusion criteria |
1. A primary diagnosis of COPD or asthma as judged by the Investigator. Patients with comorbid COPD and/or asthma can be enrolled if bronchiectasis is their primary diagnosis
2. Subjects receiving supplemental oxygen >12 hours per day.
3. Bronchiectasis due to cystic fibrosis.
4. Current smokers as defined per CDC.
5. No evidence of bronchiectasis according to the BE-CT scoring system.
6. Known or suspected immunodeficiency disorder, including history of invasive opportunistic infections (eg, TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency, or prolonged infections suggesting an immunecompromised status, as judged by the investigator.
7. Known history of HIV infection.
8. Established diagnosis of hepatitis B viral infection at the time of screening, or positive for HBsAg at the time of screening.
Subjects who have gained immunity for hepatitis B virus infection after vaccination (subjects who are HBsAg-negative, HBsAb-positive, and HBcAb-negative are eligible for the study).
Subjects with positive HBcAb are eligible for the study only if hepatitis B virus DNA level is undetectable.
9. Established diagnosis of HCV infection at the time of Screening. Subjects positive for hepatitis C antibody are eligible for the study only if HCV RNA is negative.
10. Currently being treated for NTM lung infection, allergic bronchopulmonary aspergillosis, or TB.
11. Active and current symptomatic infection by COVID-19.
12. Unable to perform technically acceptable spirometry that meet the ATS/ERS acceptability criteria with at least 3 acceptable flow-volume curves, at least 2 of which meet the ATS/ERS repeatability criteria for FEV1 during Screening.
13. Inability to follow the procedures of the study (eg, due to language problems or psychological disorders).
14. Receiving medications or therapy that are prohibited as concomitant medications
15. Started oral or inhaled antibiotics as chronic treatment for NCFBE for <3 months prior to the Screening visit.
a. Subjects on antibiotics as chronic treatment should be on such treatment for at least 3 months prior to enrollment while meeting all other inclusion criteria and none of the exclusion criteria.
16. Chronic treatment with oral steroids (irrespective of the indication)
17. Subjects who have adjustments to their baseline medications within 1 month before Screening; they can be rescreened a month after the new treatment has been initiated.
18. Abnormal renal function test result (estimated glomerular filtration rate <30 mL/min by Chronic Kidney Disease - Epidemiology Collaboration equation formula) at Screening.
19. Active liver disease or hepatic dysfunction manifested as follows:
a. Elevated liver function test results (ALT or AST >2 × ULN).
b. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
c. Known hepatic or biliary abnormalities, not including Gilbert's syndrome or asymptomatic gallstones.
20. History of malignancy in the past 5 years, except completely treated in situ carcinoma of the cervix and completely treated non-metastatic squamous or basal cell carcinoma of the skin.
21. Previously participated in a clinical trial of brensocatib.
22. An absolute neutrophil count <1,000/mm3 at the Screening Visit.
23. Received any live attenuated vaccine within 4 weeks prior to the first administration of brensocatib. If a live vaccine has been administered the subject should wait 4 weeks prior to Screening. During the study, subjects may not receive any live attenuated vaccine.
24. Significant hemoptysis (≥300 mL or requiring blood transfusion) within 6 weeks prior to the Screening Visit or during the Screening Period.
25. Have diagnosed periodontal disease and are either:
a. Under active management by a dentist for this condition or
b. Are expected to have periodontal disease-related procedures within the study period.
26. Suffering an exacerbation 4 weeks before Screening or during the Screening period. In this case, subjects will be considered a screen failure. Subjects are eligible for rescreen only after recovery and 4 weeks after last dose of antibiotic treatment
27. Unable to comply with ≥75% of completion of electronic diary entries or have compliance issues during the Screening Period.
28. Participated in any other interventional clinical studies within 3 months before Screening Visit.
29. Clinical diagnosis of Papillon-Lefevre Syndrome.
Please refer to the protocol (Section 4.1.2) for full list of the exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of PEs over the 52-week treatment period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Over the 52-week treatment period. |
|
| E.5.2 | Secondary end point(s) |
1. Time to first PE over the 52-week treatment period
2. Proportion of subjects who are exacerbation free over the 52-week treatment period
3. Change from Baseline in postbronchodilator FEV1 (defined as the average of the Screening Visit and Baseline measurements) to the average of Week 40 and Week 52 measurements.
4. Rate of severe PEs over the 52-week treatment period. (Severe exacerbations are defined as those requiring IV antibacterial drug treatment and/or hospitalization)
5. Change in QOL-B, Respiratory Symptoms Domain Score from Baseline to Week 52
6. Incidence and severity of treatment-emergent adverse events and other safety variables (eg, clinical laboratory test results, vital signs, ECG, and physical examination) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| over the 52-week treatment period. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 160 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Croatia |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Latvia |
| Lithuania |
| Malaysia |
| Mexico |
| Netherlands |
| New Zealand |
| Peru |
| Poland |
| Portugal |
| Russian Federation |
| Serbia |
| Slovakia |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
| Estonia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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