| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic obstructive pulmonary disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic obstructive pulmonary disease |
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| 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 | 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 characterize the dose response of danirixin compared with placebo on the incidence and severity of respiratory symptoms in participants with COPD
- To compare the safety of danirixin with placebo in participants with COPD |
|
| E.2.2 | Secondary objectives of the trial |
- To characterize the dose response of danirixin compared with placebo on the annual rate of moderate/severe COPD exacerbations in participants with COPD
- To further characterize the clinical activity of danirixin compared to placebo in participants with COPD
- To characterize the pharmacokinetics of danirixin in participants with COPD.
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|
| 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 40 to 80 years of age inclusive, at the time of signing the informed consent.
2. Participants who have COPD (postbronchodilator FEV1/FVC ratio < 0.7 and FEV1 % predicted ≥40%) based on American Thoracic Society (ATS)/European Respiratory Society (ERS) current guidelines. Participants with a historical diagnosis of asthma may be included so long as they have a current diagnosis of COPD.
3. History of respiratory symptoms including chronic cough, mucus hypersecretion, and dyspnea on most days for at least the previous 3 months prior to screening.
4. Participants with a documented history of COPD exacerbation(s) in the 12 months prior to study participation (screening) 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 of hospitalization or extended observation in a hospital emergency room or outpatient center and a plasma fibrinogen concentration at screening ≥3 g/L (300 mg/dL)
5. Smoking history: current 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).
Current smokers are defined as those who are currently smoking cigarettes (i.e. have smoked at least one cigarette daily or most days for the month prior to Visit 1).
Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Note: pipe and/or cigar use cannot be used to calculate smoking pack-year history.
6. Participants must have the ability and willingness to use an electronic diary (log pad) on a daily basis.
Weight
7. Body weight ≥45 kg
Sex
8. Male or female.
a. Male participants:
A male participant must agree to use contraception as detailed in appendix of the protocol, last dose of study treatment, corresponding to approximately 6 half-lives (which is the time needed to eliminate any teratogenic study treatment) and to 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
OR
(ii) A WOCBP who agrees to follow the contraceptive guidance in during the treatment period and for at least 60 hours after the last dose of study treatment.
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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. Diagnosis of other clinically relevant lung diseases (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
-A participant with a history of tuberculosis may be considered for eligibility if he/she has documented completion of a course of antibiotic therapy (eg, INH) and has no evidence of latent TB infection. A chest x-ray ideally would be available for review by the medical monitor but is not required. All cases of prior TB must be discussed with the medical monitor.
-For cancers other than lung cancer, participants may be considered for eligibility if the carcinoma has been in remission for at least 5 years. Participants who have had carcinoma in situ of the cervix, squamous cell carcinoma or basal cell carcinoma of the skin would not need to be excluded based on the 5 year waiting period if the participant has been considered cured by treatment.
2. Alpha-1-antitrypsin deficiency as the underlying cause of COPD
3. Pulse oximetry < 88% at rest at screening. Participants should be tested while breathing room air. However, participants living at high altitudes (above 5000 feet or 1500 meters above sea level) who are receiving supplemental oxygen can be included provided they are receiving the equivalent of < 4 L/min and screening pulse oximetry is measured while on their usual oxygen settings.
4. Less than 14 days have elapsed from the completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
5. A peripheral blood neutrophil count < 1.5 x 109/L.
6. Diagnosis of pneumonia (chest X-ray or CT confirmed) within the 3 months prior to screening.
7. Chest x-ray (posterior-anterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic results up to 1 year prior to screening may be used). For sites in Germany: If a chest x-ray (or CT scan) within 1 year prior to screening is not available, approval
to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office of Radiation Protection (BfS).
8. History or current evidence of other clinically significant medical condition that is uncontrolled on permitted therapies. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the participant at risk through study participation, or that would affect the safety analysis or other analysis if the disease/condition worsened during the study.
9. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
10. Abnormal and clinically significant 12-lead ECG finding. 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 study. An abnormal and clinically significant finding that would
preclude a participant from entering the study is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following
a. AF with rapid ventricular rate > 120 bpm
b. sustained or non-sustained VT
c. second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted)
d. QTcF ≥500 msec in participants with QRS < 120 msec and QTcF ≥530 msec in participants with QRS ≥120 msec
11. Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction procedure.
Prior/Concomitant Therapy
12. Current or expected chronic use of macrolide antibiotics during the study period for the prevention of COPD exacerbations. Examples of chronic use include, but are not limited to, daily or two to three times per week use for at least 3 months.
13. Oral or injectable CYP3A4 or BRCP (breast cancer resistance protein) substrates with a narrow therapeutic index (CYP3A4 substrates include, but are not limited to, alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include, but are not limited to, topotecan.) The Investigator should consult with the Medical Monitor if necessary.
14. Current or expected use of phosphodiesterase-4 inhibitors (e.g. roflumilast). Participants currently receiving roflumilast may be included if they are able to discontinue use from 30 days prior to screening through the completion of the follow up visit.
Please see Section 6.2 Exclusion Criteria in the study protocol for a complete list of exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Change from baseline in respiratory symptoms measured by E-RS:COPD daily diary: total score and subscales (i.e. breathlessness, cough and sputum, and chest symptoms)
- Adverse events (AE), clinical laboratory values, vital signs, electrocardiogram (ECG). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• E-RS: COPD at week 24
• Safety parameters – ongoing throughout the study
|
|
| E.5.2 | Secondary end point(s) |
• Healthcare Resource Utilization (HCRU)-defined COPD exacerbations
• E-RS:COPD Responder Analysis (including subscales)
• Number of Exacerbations of Chronic Pulmonary Disease (EXACT) tool defined events
• Time to first EXACT event
• EXACT event severity
• EXACT event duration for all events
• Time to first HCRU-defined COPD exacerbation
• Time to first severe HCRU-defined COPD exacerbation
• HCRU-defined exacerbation duration
• Change from baseline for the St. George’s Respiratory Questionnaire (SGRQ) total score (derived from SGRQ-C)
• SGRQ responder analysis
• Change for baseline COPD Assessment Test (CAT) total score
• CAT responder analysis
• Lung function (FEV1, FEV1 % predicted, FVC, FEV1/FVC ratio)
• Rescue medication use
• Participant experience of physical activity (subset of approximately 50% of participants) measured using PROactive Clinic Visit Tool (C-PPAC)
• Danirixin concentration and standard pharmacokinetic parameters for danirixin (e.g. AUC, Cmax, Tmax), using dried blood spot data. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 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 | 6 |
| 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 | 39 |
| 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 |
| Australia |
| Canada |
| Korea, Republic of |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 20 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 20 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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