| 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 |
| Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) |
|
| 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 | PT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 nemiralisib administered in addition to SoC compared with placebo and SoC in participants diagnosed with an acute moderate or severe exacerbation of COPD |
|
| E.2.2 | Secondary objectives of the trial |
- To characterize the dose response and efficacy of nemiralisib administered in addition to SoC compared with placebo and SoC in participants diagnosed with an acute moderate or severe exacerbation of COPD
- To evaluate the treatment effect of nemiralisib in addition to SoC compared with placebo and SoC on symptoms indicative of an exacerbation and on health status using Patient-Reported Outcomes
(PROs) in participants diagnosed with an acute moderate or severe exacerbation of COPD
- To evaluate the usage of rescue medication in patients diagnosed with an acute moderate or severe exacerbation of COPD
- To evaluate the population pharmacokinetics of nemiralisib in
participants diagnosed with an acute moderate or severe exacerbation of COPD
- To assess the safety and tolerability of nemiralisib and placebo in participants diagnosed with an acute moderate or severe exacerbation of 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. 40 to 80 years of age, inclusive, at Screening (Visit 1).
Type of Participant and Disease Characteristics
2. Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society [GOLD, 2017] as follows:
“Chronic obstructive pulmonary disease is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.”
3. Smoking History: Current or former cigarette smoker with a history of cigarette smoking of ≥10 pack-years. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Screening (Visit 1). Number of pack years = (number of cigarettes per day / 20) x number of years smoked) (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack-years)
4. Current Acute Exacerbation of COPD: Acute exacerbation of COPD requiring an escalation in therapy to include oral/systemic corticosteroid(s) (prednisone 40 mg/day or equivalent) for 5 days and antibiotic(s) for 7 days; the dose and/or duration of prednisone (40 mg/day or equivalent) and/or the antibiotic can be modified according to the Investigator’s/medically qualified designee’s judgement or according to local country/institution practice. Acute exacerbation to be confirmed by an experienced physician and to represent a recent worsening of at least two major and one minor symptoms, one major and two minor symptoms, or all 3 major symptoms.
i. Major symptoms:
i. Subjective increase in dyspnea
ii. Increase in sputum volume
iii. Change in sputum colour
ii. Minor symptoms:
i. Increased cough
ii. Increased wheeze
iii. Sore throat
iv. Colds (nasal discharge and/or nasal congestion)
v. Fever (oral temperature >37.5°C) without other cause
Weight
5. Body Mass Index: Body weight ≥45 kg and body mass index (BMI) within the range 16 – 35 kg/m2 (inclusive)
Sex
6. Male and female subjects are eligible to participate in the study.
a. Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 5 of the protocol),
not breastfeeding, and at least one of the following conditions applies:
i. Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 of the protocol
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 of the protocol during the 12-Week Double-Blind Treatment Period and for at least 5 halflives (10 days) after the last of double-blind study treatment.
Informed Consent
7. Capable of giving signed informed consent as described in Appendix 3 of the protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Asthma: Current diagnosis of asthma, according to the Global Initiative for Asthma [GINA, 2017]. Participants with a prior history of asthma are eligible if they have a current diagnosis of COPD.
2. Acute respiratory acidosis/invasive mechanical ventilation: pH < 7.30 or the need for invasive mechanical ventilation.
3. Moderate/severe exacerbation of COPD for which SoC was started >48 hours since diagnosis.
4. Chest X-ray (or CT scan): A chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray (or CT scan) must be taken at Screening (Visit 1). For sites in Germany: if a chest X-ray (or CT scan) within 1 year of Screening (Visit 1) is not available, approval to conduct a diagnostic chest X-ray (CT scan) will need to be obtained from the Federal Office for Radiation Protection (BfS).
5. Pneumonia: Clinically significant pneumonia, identified by chest X-ray (CT scan) at Screening
6. Other respiratory disorders: A diagnosis of α1-antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, clinically overt bronchiectasis (Note: focal bronchiectasis is not exclusionary), sarcoidosis, pulmonary fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), primary pulmonary hypertension, interstitial lung diseases,or any other respiratory condition that might, in the opinion of the investigator, compromise the safety of the subject or affect the interpretation of the results.
7. Other diseases/abnormalities: A history or current evidence of clinically significant and unstable disease such as cardiovascular (e.g., patients requiring implanted cardioverter defibrillator [ICD], pacemaker requiring a rate set >60bpm, uncontrolled hypertension, New Your Heart Association Class IV [NYHA, 1994], known left ventricular ejection fraction <30%) neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease), peptic ulcer disease, or haematological abnormalities. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. (Note: Participants with adequately treated and well controlled concurrent medical conditions (e.g. hypertension or noninsulin-dependent diabetes mellitus [NIDDM]) are permitted to be entered into the study).
8. Lung resection: Having undergone lung volume reduction surgery or lung resection for any other reason e.g. lung carcinoma
9. Liver disease:
• ALT > 2xULN
• Total Bilirubin > 1.5xULN
• Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%
• Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones)
• Presence of hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to first dose of study treatment
• Positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment
• Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
• NOTE: due to time taken to conduct Hepatitis B and C analysis, participants may be randomised to the study before receiving these results. If a participant has a positive test result, they will need be withdrawn promptly from the study.
10. Positive hepatitis C RNA test result at Screening or within 3 months prior to first dose of study treatment. NOTE: Test is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing
11. Cancer: Carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin are not excluded if the participant has been considered cured within 5 years since diagnosis.
12. Contraindications: History of allergy or hypersensitivity to any of the study medications (e.g. beta-agonists, PI3Kd inhibitors) or components of the inhalation powder (e.g., lactose). In addition, participants with a history of severe milk protein allergy that, in the opinion of the investigator, contraindicates the participant’s participation are excluded.
For remaining exclusion criteria points 13 to 26 please refer to the protocol P 54-57. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Change from baseline in Clinic Visit trough forced expiratory volume in one second (FEV1) at Day 84 measured postbronchodilator
- Baseline is defined as the postbronchodilator FEV1 measured prior to the first dose of double-blind study treatment and post-bronchodilator on Day 1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Rate of moderate and severe exacerbations over the 12-Week Treatment Period
- Time to next moderate/severe exacerbation following index exacerbation
- Change from baseline in Clinic Visit trough FEV1 measured pre and post-bronchodilator at Days 14, 28, 56, and 84 (Day 84: postbronchodilator is the primary endpoint; prebronchodilator
is a secondary endpoint) and at hospital discharge (only for participants who are hospitalized for the index exacerbation)
- Change from hospital discharge in clinic visit trough FEV1 measured pre- and postbronchodilator at Days, 14, 28, 56, and 84
(in participants hospitalized for index exacerbation only) EXAcerbations of Chronic Pulmonary Disease Tool (EXACT-PRO)
- Proportion of participants achieving the EXACT definition of recovery from the index exacerbation by Days 14, 28, 56, and 84
- Time to recovery from index exacerbation
- Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT COPD Assessment Test (CAT)
- Proportion of responders using the CAT at Treatment Days 28, 56, and 84, and following EXACT defined recovery from the index exacerbation
- Change from baseline (Day 1) in CAT total score at Days 28, 56, and 84 and following EXACT defined recovery from the index exacerbation
St. George’s Respiratory Questionnaire (SGRQ) Total Score
- Proportion of responders on the St. SGRQ total score as measured by the SGRQ for COPD Patients (SGRQ-C) at Days 28, 56, and 84
- Change from baseline (Day 1) in SGRQ total score at Days 28, 56, and 84
- Rescue medication use (occasions/day), averaged over each week of treatment and over the 84-day treatment period
- The percentage of rescue-free days (24- hour periods) during each week of treatment and over the 84-day treatment period
- Plasma nemiralisib concentrations and derived PK parameters (e.g., area under the curve [AUC (0-24) and AUC(0-t)], maximum
concentration [Cmax], time at maximum concentration [Tmax], Ctrough) as appropriate will be collected in a subset of randomized participants (approximately 300) at selected sites as follows: trough
(pre-dose) for the study treatment and postdose for the study treatment from 0-1 hour and >1 to 6 hours on Days 14 and 28 of the
12-Week Treatment Period
- Incidence of adverse events (AEs; including serious AEs and AE of Special Interest [AESI])
- Vital signs (pulse rate, systolic and diastolic blood pressure) (measured at each clinic visit up through Visit 7 [Day 112] or Early
Withdrawal Visit)
- 12-lead electrocardiogram (ECG) assessments (performed at clinic Visits 1 [Screening], 3 [Day 14], 6 [Day 84], and 7 [Day 112] or Early Withdrawal Visit)
- Clinical laboratory tests (hematology and chemistry; performed at each clinic visit up through Visit 7 [Day 112] or Early Withdrawal Visit)
- Incidence of COPD exacerbations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Days 14, 28, 56, 84 and 112 |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 99 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 | 2 |
Print
