E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic obstructive pulmonary disease |
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E.1.1.1 | Medical condition in easily understood language |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 100000015472 |
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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 assess the change from baseline in NETs formation in participants with COPD following 14 days treatment with danirixin HBr 35mg twice daily |
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E.2.2 | Secondary objectives of the trial |
-To assess the change from baseline in NETs formation in participants with COPD following 14 days treatment with danirixin HBr 35mg twice daily
-To further characterize the safety of danirixin HBr 35mg twice daily compared with placebo in participants with COPD.
-To assess the effects of danirixin HBr 35mg twice daily on NET osis- associated biomarkers in sputum and peripheral blood
-Characterise the population pharmacokinetic (PK) profile of
approximately 14 days of dosing of danirixin HBr 35mg twice daily in participants with COPD |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 50 to 75 years of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Diagnosis of COPD with mild to moderate airflow obstruction (post-bronchodilator FEV1/ Forced Vital Capacity (FVC) ratio <0.7 and FEV1% predicted (pred) ≥40% at screening) based on the Quanjer reference equations, with spirometry conducted according to American Thoracic Society (ATS)/European Respiratory Society (ERS) current guidelines.
3. Elevated sputum neutrophil extracellular traps based on screening assay for histone-elastase complexes of >0.5 units/ml sputum. Two further screening samples can be submitted for analysis within 30day screening period if previous samples do not pass criteria.
4. Able to produce at least 1ml of sputum sample at the screening visit with nebulised saline induction
5. Current smokers and former smokers with a cigarette smoking history of ≥10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
Weight
6. Body weight ≥ 45 kg
Sex
7. Male or female
a. Male participants:
A male participant must agree to use contraception as detailed in protocol during the treatment period and for at least [60 hours, corresponding to approximately 6 half-lives which is the time needed to eliminate any teratogenic treatments after the last dose of study treatment and refrain from donating sperm during this period]
b. Female participants:
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
(i) Not a woman of childbearing potential (WOCBP) as defined in the protocol
OR
(ii) A WOCBP who agrees to follow the contraceptive guidance in protocol
during the treatment period and for at least 60 hours after the last dose of
study treatment.
Informed Consent
8. Capable of giving signed informed consent as described in protocol which
includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
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E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Primary clinical diagnoses of any of the following relevant lung diseases; asthma, sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer
2. Known alpha-1-antitrypsin deficiency
3. Pulse oximetry <88% at rest at screening. Participants should be tested while breathing room air.
4. Participants on long term oxygen therapy (defined as >15 hours/day of oxygen use)
5. Unstable co-morbidities (eg cardiovascular disease, active malignancy) which in the opinion of the Investigator would make the participant unsuitable to be enrolled in the study. This includes any abnormality identified on screening bloods or screening ECG which in the opinion of the Investigator would make the participant unsuitable for the study
6. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator of GSK medical monitor, contraindicates their participation.
7. Current or chronic history of liver disease, or know hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
8. Participants with a known or suspected history of alcohol or drug abuse within the last 2 years
Prior/Concomitant Therapy
9. Antibiotic use concurrently or within 28 days preceding the screening visit, including current or planned chronic use of macrolide antibiotics during the study period for the prevention of COPD exacerbations. Examples of chronic use include daily or
two-three times per week for at least 3 months
10. Systemic immunosuppressive medication, including current oral corticosteroids at a dose >5mg, concurrently or within 28 days preceding the screening visit.
11. Oral or injectable Cytochrome P450 (CYP) 3A4 or Breast Cancer Resistance Protein (BCRP) substrates with narrow therapeutic index (CYP3A4 substrates include, but are not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include: Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin,
sulfasalazine, topotecan..
12. Current use of phosphodiesterase-4 inhibitors: Roflumilast, Crisaborole and Apremilast
13. Current use of Raloxifene
14. Current use of low molecular weight heparin
Prior/Concurrent Clinical Study Experience
15. The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half lives, or twice the duration of the biological effect of the
investigational product (whichever is longer).
16. Exposure to more than four investigational products within 12 months prior to the first dosing day.
Diagnostic assessments
17. Participants with a peripheral blood neutrophil count < 1.0 x 109/L at screening
18. Diagnosis of pneumonia (chest X-ray or computed tomography [CT] confirmed) within the 3 months prior to screening
19. Chest X-ray (posterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic data
up to 1 year may be used).
20. Abnormal and clinically significant 12-lead ECG finding at screening. The investigator will determine the clinical significance of each abnormal ECG finding in relation to the participant’s medical history and exclude participants who would be at
undue risk by participating in the trial. An abnormal and clinically significant finding that would preclude a participant from entering the trial is defined as a 12- lead tracing that is interpreted as, but not limited to, any of the following:
-AF with rapid ventricular rate > 120 beats per minute (bpm);
-sustained or non-sustained ventricular tachycardia (VT)
-second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted)
-QT interval corrected for heart rate by Fridericia’s formula (QTcF)≥ 500 msec in participants with QRS <120 msec and QTcF ≥ 530
millisecond (msec) in participants with QRS ≥ 120 msec
Other Exclusions
21. Affiliation with a study site: study investigators, sub-investigators, study coordinators, employees of a study investigator, sub-investigator or study site, or immediate family members of any of the above that is involved with the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Reduction in sputum NETs (quantified by Histone-elastase complexes) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, baseline, day 7 and day 14(end of treatment) |
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E.5.2 | Secondary end point(s) |
-Reduction in sputum NETS (quantified by Deoxyribonucleic acid [DNA]-elastase complexes)
-Reduction in sputum NET area quantification by microscopy
-Adverse events
-Vital Signs
-ECG
- Spirometry
-Clinical Laboratory Assessments (hematology, clinical chemistry,
urinalysis)
-Change from baseline in sputum resistin levels
-Change from baseline in the ratio of sputum NETs to sputum neutrophils
-Change from baseline in sputum elastase activity
-Change from baseline in peripheral blood neutrophil NET formation (DNA release, microscopy)
-Model specific PK parameters of danirixin (e.g., oral clearance, oral steady state volume of distribution). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, baseline, day 7 and day 14(end of treatment) |
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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 | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 8 |