| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD)/chronic bronchitis and emphysema |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease (COPD)/chronic bronchitis and emphysema |
|
| 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 | 10010953 |
| E.1.2 | Term | COPD exacerbation |
| 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 clinical efficacy of nemiralisib compared with placebo to reduce the annual rate of moderate and
severe exacerbations in participants with COPD. |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the effect of nemiralisib compared to placebo on further efficacy parameters pertaining to exacerbations
and aligned with the primary objective
-To evaluate the effect of nemiralisib
compared with placebo on respiratory symptoms and Health related quality of life (HRQoL) using Patient Reported Outcomes (PROs)
-To evaluate the effect of nemiralisib compared to placebo on lung function
- To evaluate the effect of nemiralisib compared to placebo on rescue medication use
-To evaluate the population pharmacokinetics of nemiralisib
-To evaluate the safety and tolerability of nemiralisib compared with placebo |
|
| 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 the following criteria apply:
Age
1. ≥40 and ≤ 80 years of age inclusive, at the time of signing the informed consent.
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 common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflowlimitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.”
3. Documented history of COPD exacerbation (s): ≥ 2 moderate exacerbations (prescription for antibiotics and/or oral corticosteroids) or ≥ 1 severe exacerbation
(hospitalisation or visit to the emergency room) in the 12 months prior to study participation Screening (Visit 1)
4. 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
5. Symptomatic COPD: A score of ≥ 10 on the COPD Assessment Test (CAT) at Screening (Visit 1).
Existing prescribed inhaled COPD maintenance therapy: Must be receiving a stable daily inhaled COPD maintenance therapy for their COPD for at least 3 months prior to Screening (Visit 1). Participants may continue their prescribed inhaled maintenance COPD therapy throughout the study (Run-in and Treatment Periods).
Note: Participants receiving only PRN COPD medications are not eligible.
6. Must have a post-bronchodilator (albuterol/salbutamol) FEV1/ (forced vital capacity)
(FVC) ratio ≤ 0.70 and post-bronchodilator FEV1 ≤ 80% of predicted [Quanjer, 2012] documented in the last 5 years.
7. Must not be taking antibiotics and/or oral corticosteroids for a COPD exacerbation
within 6 weeks prior to Screening (Visit 1).
8. Able to perform lung function tests reliably.9. Must have the ability to use an electronic diary on a daily basis.
Weight
10. Body weight ≥ 45 kg and body mass index (BMI) within the range of 16-35 kg/m2 (inclusive).
Sex
11. Male and female participants 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 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 protocol OR
(ii) A WOCBP who agrees to follow the contraceptive guidance inAppendix 5 of protocol during the 12-Month Double-Blind Treatment Period and for at least 5 half- lives (10 days) after the last dose of double-blind study
treatment. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Informed Consent
12. Capable of giving signed informed consent as described in Appendix 3 of 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. Current diagnosis of asthma, according to the Global Initiative for Asthma [GINA, 2017].
2. Less than 6 weeks elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
3. 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) (or historic radiograph or CT scan obtained within 3 months prior to screening). 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).
4. Diagnosis of Pneumonia (chest X-ray or CT confirmed) within the last 3 months prior to Screening (Visit 1).
5. Other respiratory disorders: A diagnosis of α1-antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis (Note:
focal bronchiectasis is not exclusionary), sarcoidosis, active tuberculosis, lung cancer, clinically overt bronchiectasis (Note: focal bronchiectasis is not
exclusionary), 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.
6. Other diseases/abnormalities: A history or current evidence of clinically significant and unstabledisease 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 hematological abnormalities. Significant is defined as anydisease 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).
7. Lung resection: Having undergone lung volume reduction surgery or lung resection for any other reason (e.g. lung carcinoma)
8. Liver disease
a. ALT > 2xULN
b. Total Bilirubin > 1.5xULN
i. Isolated bilirubin >1.5xULN is acceptable if bilirubin is
fractionated and direct bilirubin <35%
c. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones
d. Presence of hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to first dose of study treatment
e. Positive hepatitis C antibody test result at Screening orwithin 3 months prior to first dose of study treatment
f. 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.
9. 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
10. 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.
11. Contraindications: History of allergy or hypersensitivity to any of the studymedications (e.g. beta-agonists, PI3Kd inhibitors). In addition, participants with a
history of severe milk protein allergy (e.g lactose) that, in the opinion of the investigator, contraindicates the participant’s participation are excluded.Prior/Concomitant Therapy
12. Use of the following medications:
- Strong inhibitors of cytochrome P450 3A4: Currently, only in vivo information is available on the in vivo metabolism of nemiralisib; and, the role of cytochrome P450s (CYPs) in the elimination of nemiralisib is based upon in vitro data. In vitro studies indicate that nemiralisib is predominantly metabolized by CYP3A4 enzymes with minor contributions from CYP1A1,CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2J2.
Refer Protocol for other exclusions points |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Annualised rate of on-treatment moderate and severe exacerbations as defined by Health Care Resources Utilization (HCRU) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluated at 8 clinic visits over a 52-week treatment period |
|
| E.5.2 | Secondary end point(s) |
Annualised rate of on-treatment HCRU/EXACT defined mile, moderate, and severe exacerbations
Time to first on treatment HCRU/EXACT defined moderate/severe exacerbation
Time to first on treatment HCRU/EXACT defined mild/moderate/severe exacerbation
Evaluating Respiratory Symptoms (E-RS) in COPD (E-RS: COPD)
Change from baseline in monthly weighted mean of E-RS: COPD (Total score and sub domains)
- Proportion of responders according to ERS:
COPD (Total score and sub domains)
COPD Assessment Test (CAT)
- Proportion of responders according to CAT
at Weeks 4, 12, 28, 52
- Change from baseline in CAT total score at
Weeks 4, 12, 28, 52
St. George’s Respiratory Questionnaire total score (measuring using SGRQ for COPD Patients (SGRQ-C))
- Proportion of responders SGRQ-C total score at Weeks 4, 12, 28, 52
- Change from baseline SGRQ-C total score at Weeks 4, 12, 28, 52
Exacerbations of Chronic Pulmonary Disease Tool (EXACT)
- Annualised rate of HCRU/EXACT events
- Time to first HCRU/EXACT event
- Severity and duration of each
HCRU/EXACT event
- Change from baseline in clinic visit trough pre-and post-bronchodilator Inspiratory
Capacity (IC), FEV1, and FVC, at Weeks, 4, 12, 28, 52
Rescue Medication Use (occasions/day)
- The percentage of rescue-free days (24- hour periods) during each month of treatment and over the 12 Month Treatment Period
PK concentrations and parameters
- 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 Week 52 or Early Withdrawal Visit
- 12-Lead ECG performed at Screening, Weeks 4, 12, 28, 52 or Early Withdrawal Visit
- Clinical laboratory evaluations
(haematology, clinical chemistry, urinalysis) performed at each clinic visit up through
Week 52 or Early Withdrawal
- Incidence of COPD exacerbations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluated at 8 clinic visits over a 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 | No |
| 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 | No |
| 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 | 8 |
| 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 |
| Argentina |
| Germany |
| Mexico |
| Poland |
| Spain |
| Sweden |
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 24 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
Print
