| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) |
|
| 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 | 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 efficacy of inhaled AZD8871 600 µg in patients with moderate to severe COPD |
|
| E.2.2 | Secondary objectives of the trial |
| To investigate the PK of AZD8871 600 µg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of signed and dated, written ICF prior to any study-specific procedures, sampling, and analyses.
2. Patient must be 40 to 85 years of age (both inclusive) at the time of signing the ICF (Screening; Visit 1).
3. COPD Diagnosis: Patient with an established clinical history of moderate to severe COPD for more than 1 year at Screening, according to the GOLD COPD guidelines.
4. Tobacco Use: Patient is a current or former smoker with a history of ≥10 pack-years of cigarette smoking [Number of pack-years=(number of cigarettes per day/20)* number of years smoked (eg, 1 pack-year=20 cigarettes smoked per day for 1 year)]. A former smoker is defined as one who has stopped smoking for at least 6 months prior to Screening.
- Patient smoking other tobacco types (including e-cigarettes) will not be allowed, unless he/she meets the cigarette criterion as well.
5. Patient with post-bronchodilator FEV1/forced vital capacity (FVC) ratio <70% based on the value reached after inhalation of salbutamol (400 µg) at Visit 2. If criterion is not met, the test can be repeated at the latest, up to Day -14.
6. Patient with post-bronchodilator FEV1 that must be ≥40% and <80% predicted normal value at Visit 2. If criterion is not met, the test can be repeated at the latest, up to Day -14.
7. Patient is willing and, in the opinion of the Investigator, able to change current COPD therapy as required by the protocol and willing to use ipratropium following the approved dosage and regimen (during run-in and wash-out periods) with or without ICS for maintenance therapy of COPD and rescue medication salbutamol (as needed) from Visit 1 to Visit 11.
8. Patient must be able to read, speak and understand local language, and be willing to remain at the study centre as required per-protocol to complete all visit assessments.
9. Body mass index (BMI) <40 kg/m2 at the time of Screening.
10. Male and/or females of non-childbearing potential who are not pregnant or lactating.
11. Female patients must be of non-childbearing potential defined as:
- Permanently or surgically sterilised, including hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy.
- Post-menopausal; aged <50 years and amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post menopausal range of the local laboratory.
- Post-menopausal; aged ≥50 years and amenorrhoeic for 12 months or more, following cessation of all exogenous hormonal treatments.
12. Male patients should use a condom and spermicide (or sexual abstinence*) to prevent pregnancy and drug exposure of a partner, regardless of the gender or childbearing potential of the partner from the day of the first administration of the IP until 3 months after the last administration of the IP. In addition to a condom with spermicide, a second highly effective method of contraception (oral, intravaginal or transdermal hormonal contraceptives, intrauterine device, or intrauterine hormone-releasing system, or sexual abstinence until 3 months after the last administration of the IP) should be used with female partners of childbearing potential. Double barrier methods (a combination of male condom with either a cap, diaphragm or sponge with spermicide) are not considered to be highly effective methods of contraception. Male patients with a pregnant partner should use a condom and spermicide or sexual abstinence*.
*True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception). |
|
| E.4 | Principal exclusion criteria |
1. Patient has significant diseases other than COPD, (ie, clinically relevant disease or condition or an abnormality in prior ECGs, medical history or physical examinations) which, in the opinion of the Investigator, may put the patient at risk because of participation in the study or may influence either the results of the study or the patient's ability to participate in the study.
2. Patient has alpha-1 antitrypsin deficiency as the cause of COPD.
3. Patient has other active pulmonary disease such as predominant asthma, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep apnoea. Allergic rhinitis is not exclusionary.
4. Lung surgery for volume reduction or lung transplantation: Patient has undergone lung volume reduction surgery, lobectomy, or bronchoscopic lung volume reduction (endobronchial blockers, airway bypass, endobronchial valves, thermal vapour ablation, biological sealants, massive pulmonary embolism and airway implants) within 1 year of Screening (Visit 1).
5. Patient is using nocturnal positive pressure (eg, continuous positive airway pressure or bi level positive airway pressure). Patient is using any non-invasive positive pressure ventilation device.
6. Patient who had 2 or more exacerbations of COPD (moderate or severe in intensity) within the last year prior to Screening (see Section 7.1 for definition of exacerbation of COPD).
7. Patient has been hospitalised due to poorly controlled COPD within 3 months of the Screening period.
8. Patient has acute worsening of COPD that requires treatment with corticosteroids or antibiotics in the 6 week interval prior to or during the Screening period.
9. Patient has had lower respiratory tract infection(s) that required antibiotics within 6 weeks prior to the Screening period.
10. Patient has significant cardiovascular disease that may be vulnerable to cardiovascular instability.
11. Patient with a QT interval corrected using Fridericia's formula (QTcF) value >450 ms for male and >470 ms for female or an ECG that is not suitable for QT measurements (eg, poorly defined termination of the T wave).
12. Patient with a heart rate <50 or >100 beats per minute (bpm).
13. Patient has clinically significant uncontrolled hypertension (>160 mmHg) as assessed by the Investigator.
14. Patient has seizures or a history of seizures requiring anticonvulsants within 12 months prior to Screening.
15. Patient is taking selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors whose dose has not been stable for at least 4 weeks prior to Screening, or exceeds the maximum recommended dose.
16. Patient has a symptomatic bladder neck obstruction, acute urinary retention or symptomatic non-stable prostate hypertrophy.
17. Any laboratory abnormality or suspicion of any clinically relevant disease or disorder (on history or examination), including uncontrolled diabetes or hypokalaemia (serum potassium <3.5 mmol/L), which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient’s ability to participate in the study, or any other safety concerns in the opinion of the Investigator. Note: Potassium replacement and re-test is allowed once if serum potassium concentration was <3.5 mmol/L at Screening or prior to randomisation.
18. Patient has known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C infection.
19. History of malignancy of any organ system, treated or untreated within the past 5 years, with the exception of localised basal cell carcinoma of the skin.
20. Patient has known narrow-angle glaucoma.
21. Patient has a history of drug of abuse within the past 2 years or consuming more than 14 (female patients) or 21 (male patients) units of alcohol a week, or shows positive for drugs of abuse and alcohol tests at Screening and prior to randomisation.
22. Patient has a history of hypersensitivity (including paradoxical bronchospasm) to β2-agonists, muscarinic anticholinergics or lactose/milk protein. Lactose intolerance is not an exclusion criterion.
23. Patient has received a live attenuated vaccination within 30 days prior to Screening.
24. Patient who, in the opinion of the Investigator, is unable to abstain from protocol-defined prohibited medications during the study.
25. Patient was treated with an investigational drug or device in another clinical trial within the last 30 days or 5 half-lives (whichever is longer) prior to Screening.
26. Previous participation or prior screen failure in the present study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in Trough FEV1 on Day 15. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• FEV1 AUC(0-4)/4h (area under the curve for the change in FEV1from baseline to 4h, normalised by the time window) at Day 1, Day 8, and Day 14.
• FEV1 AUC(0-8)/8h, AUC(0-12)/12h, and AUC(0-24)/24hat Day 1 and Day 14.
• Change from baseline in Trough FEV1 on Day 2, and Day 8.
• Change from baseline in Peak FEV1 on Day 1, Day 8 and Day 14.
• Change from baseline in Trough FEV1 over treatment duration.
• Change from baseline in Peak FEV1 over treatment duration.
• Change from baseline in Total Score of BCSS questionnaire and cough, breathlessness and sputum individual domain scores from Day 1 to Day 8, from Day 9 to Day 14 and during the whole treatment duration.
• Change from baseline in CAT from Day 1 to Day 8, from Day 9 to Day 14 and during the whole treatment duration.
• Rescue medication use from Day 1 to Day 8 and from Day 9 to Day 14.
On serial PK sampling days, the following PK parameters will be calculated for AZD8871 and its primary metabolite LAS191861 when applicable:
Day 1: Maximum plasma concentration (Cmax), time to reach maximum plasma concentration (tmax), area under the plasma concentration-curve from time 0 to the time of last quantifiable concentration (AUClast), area under the plasma concentration-curve from time 0 to 24 hours post dose AUC(0-24).
Day 14: Cmax, tmax, AUClast, AUC(0-24), average plasma concentration during a dosing interval (Cavg,), fluctuation index during a dosing interval (%Fluctuation), accumulation ratio for Cmax [Rac(Cmax)] and accumulation ratio for AUC(0-24) [Rac(AUC(0-24))]. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At specific time points during the study and over treatment duration. |
|
| 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 | 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 | Yes |
| 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) | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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
|
|
| 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 | 12 |
| 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 | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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