| 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 |
| Chronic Obstructive Pulmonary Disease |
|
| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| 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 |
Primary-Part A & Part B
To evaluate the safety and tolerability of danirixin compared with placebo in symptomatic COPD subjects with mild to moderate airflow limitation
Primary -Part A
To characterize the pharmacokinetics of danirixin in symptomatic COPD subjects with mild to moderate airflow limitation
Primary-Part B
To characterize the effect of danirixin compared with placebo on the incidence and severity of respiratory symptoms and COPD exacerbations in symptomatic COPD subjects with mild to moderate airflow limitation |
|
| E.2.2 | Secondary objectives of the trial |
Secondary- Part B
To characterize the pharmacokinetics of danirixin in symptomatic COPD subjects with mild to moderate airflow limitation
To further characterize clinical efficacy of danirixin in symptomatic COPD subjects with mild to moderate airflow limitation
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Male or female aged between 40 and 75 years of age inclusive, at the time of signing the informed consent
2. Subjects with a documented history of COPD exacerbation(s) in the 12 months prior to study participation meeting at least one of the following criteria:
•≥ 2 COPD exacerbations resulting in prescription for antibiotics and/or oral corticosteroids or hospitalization or extended observation in a hospital emergency room or outpatient center
•1 COPD exacerbation resulting in prescription for antibiotics and/or oral corticosteroids or hospitalization or extended observation in a hospital emergency room or outpatient center and a plasma fibrinogen concentration at screening ≥ 3 mg/mL
3. Diagnosis of symptomatic chronic obstructive pulmonary disease with mild to moderate airflow obstruction (COPD-GOLD I or II) for at least 2 years based on American Thoracic Society (ATS)/ European Respiratory Society (ERS) current guidelines or symptoms consistent with COPD for at least 2 years
4. Subjects with a post-bronchodilator FEV1/FVC ratio of < 0.7 and FEV1 ≥ 50% of predicted normal value calculated using NHANES III reference equation at Visit 1 [Hankinson, 1999; Hankinson, 2010]
5. A female subject is eligible to participate if she is of:
Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, “documented” refers to the outcome of the investigator's/designee’s review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) will not be enrolled in the study.
6. Body weight ≥ 45 kg
7. 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
8. Subjects with a history of respiratory symptoms, including chronic cough and/or mucus hypersecretion on most days for at least the previous 3 months prior to Visit 1
9. AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
10. Able to perform lung function tests reliably
11. Based on single or averaged QTc values of triplicate ECGs obtained over a brief recording period:
•QTcF < 450 msec; or
•QTc < 480 msec in subjects with Bundle Branch Block
12. Subjects must have the ability to use an electronic diary on a daily basis [Part B only]
13. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
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|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Diagnosis of asthma, or other clinically relevant lung disease (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
•Subject with alpha-1-antitrypsin deficiency as the underlying cause of COPD
2. Pulse Oximetry levels <88% (at rest on room air) at screening. Subjects should be tested while breathing room air. However, subjects living at high altitudes (above 5000 ft or 1,500 m) who are receiving supplemental O2 can be included provided they are receiving the equivalent of <4L/min and screening oximetry is measured while on their usual settings.
3. Less than 14 days have elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
4. Diagnosis of Pneumonia (chest X-Ray or CT confirmed) within the last 3 months prior to screening
5. History or current evidence of clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension or any other clinically significant cardiovascular, neurological, endocrine, or hematological abnormalities that are uncontrolled on permitted therapy. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the subjects at risk through study participation, or which would affect the safety analysis or other analysis if the disease/condition exacerbated during the study.
6. A positive pre-study drug/alcohol screen
7. A positive test for HIV antibody
8. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
9. 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 or GSK Medical Monitor, contraindicates their participation
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
11. History of regular alcohol consumption within 6 months of the study defined as:
•For non US sites: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
•For US sites: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
12. Current or expected use of proton pump inhibitors or histamine H2-receptor antagonists during the study period
13. Chest X-ray (posteroanterior with lateral) or CT scan reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD (historic data up to 1 yr may be used).
14. Subjects with peripheral blood neutrophil count (PBN) <2x109/L
15. Subject with history of previous lung surgery (e.g. lobectomy, pneumonectomy, or lung volume reduction)
16. Requiring the use of oral or injectable CYP3A4 or BCRP substrates with a narrow therapeutic index (refer to Section 5.11.2.)
17. Current or expected chronic use of macrolides during the study period for the prevention of COPD exacerbations. Examples of "chronic use" would be daily or two-three times per week for at least 3 months. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary-Part A & Part B
•Adverse Events (AEs)
•Vital Signs
•ECG
•Clinical laboratory evaluations (hematology, clinical chemistry, urinalysis)
•Lung Function (spirometry)
Primary -Part A
Standard pharmacokinetic parameters for danirixin (i.e. AUC, Cmax, Tmax)
Primary-Part B
•Health Care Resource Utilization (HCRU) defined COPD exacerbations (new prescription antibiotics or oral corticosteroids, hospitalization or emergency room visits for management of COPD exacerbation)
•Monthly weighted means of EXACT Respiratory Symptoms (EXACT-RS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 0, 2, 4, 8, 12, 16, 20, 24, 32, 40, 52, 56 |
|
| E.5.2 | Secondary end point(s) |
Part B
•Standard pharmacokinetic parameters for danirixin (i.e.AUC, Cmax, Tmax)
•EXACT-PRO event
•EXACT-PRO total score weighted means
•Time to first HCRU COPD exacerbation
•Time to first moderate HCRU COPD exacerbation
•Time to first severe HCRU COPD exacerbation
•Time to first EXACT-PRO event
•EXACT-PRO events severity and duration
•Monthly weighted mean EXACT-RS domain scores (breathlessness, cough & sputum, chest symptoms)
•COPD Assessment Test (CAT)
•Lung function (spirometry)
•Physician Global Assessment
•Patient Global Rating of Severity
Patient Global Impression of Change
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 0, 2, 4, 8, 12, 16, 20, 24, 32, 40, 52, 56 |
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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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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
| 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 | 2 |
| 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 | 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 |
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| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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