Chronic Obstructive Pulmonary DiseasePhase 2NCT03645434
A Single Inhalation Dose Study to Assess Efficacy, Pharmacokinetics (PK), Safety and Tolerability of AZD8871 in Patients With Long-term Lung Diseases.
A Phase 2 study testing AZD8871 and Anoro® Ellipta® in people with Chronic Obstructive Pulmonary Disease, run by AstraZeneca at 5 sites in 2 countries.
Trial summary
This study will evaluate the efficacy and safety data of AZD8871 in patients with moderate to severe chronic obstructive pulmonary disease (COPD). This study will determine the 24-hour efficacy (lung function) profile of AZD8871 600 μg relative to placebo dry powder inhaler (DPI) based on trough forced expiratory… Read more about this study
- Who is it for?
- Ages 40 to 85 years
- Conditions the study is for
- Chronic Obstructive Pulmonary Disease
- What is being tested?
- AZD8871 and Anoro® Ellipta®
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 73 participants
- Where
- 5 sitesin 2 countries
- Study dates
- 10 Oct 2018to 7 Aug 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Provision of signed and dated, written ICF prior to any study-specific procedures, sampling, and analyses.
- Patient must be 40 to 85 years male and/or females of non-childbearing potential who are not pregnant/lactating at the time of signing the ICF (Screening; Visit 1).
- Patient with an established clinical history of moderate to severe COPD for more than 1 year at Screening, according to the GOLD COPD guidelines.
- Patient who is a current or former smoker (defined as one who has stopped smoking for at least 6 months prior to Screening) 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)].
- 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.
- 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.
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- 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.
- 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.
- Body mass index (BMI) <40 kg/m2 at the time of Screening.
- 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.
- Male patients should use a condom and spermicide 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, 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.
Who cannot join
- 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.
- Patient has alpha-1 antitrypsin deficiency as the cause of COPD.
- 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.
- 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).
- 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. Note: A patient using continuous positive airway pressure or bi level positive airway pressure for Sleep Apnoea Syndrome is allowed in the study.
- 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).
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- Patient has been hospitalised due to poorly controlled COPD within 3 months of the Screening period.
- 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.
- Patient has had lower respiratory tract infection(s) that required antibiotics within 6 weeks prior to the Screening period.
- Patient has significant cardiovascular disease that may be vulnerable to cardiovascular instability. Note: Some examples of clinically significant cardiovascular conditions are:
- Myocardial infarction within the 6 months prior to Screening Visit (Visit 1).
- Unstable angina or unstable arrhythmia which has required changes in the pharmacological therapy or other intervention within 12 months prior to Screening (Visit 1), or newly diagnosed arrhythmia within the previous 3 months prior to Screening (Visit 1).
- Second degree atrio-ventricular block.
- Use of pacemaker.
- Hospitalisation within 12 months prior to Screening (Visit 1) for heart failure functional classes III (marked limitation of activity and only comfortable at rest) and IV per the "New York Heart Association".
- 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).
- Patient with a heart rate <50 or >120 beats per minute (bpm).
- Patient has clinically significant uncontrolled hypertension (>180 mmHg) as assessed by the Investigator.
- Patient has seizures or a history of seizures requiring anticonvulsants within 12 months prior to Screening.
- 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.
- Patient has a symptomatic bladder neck obstruction, acute urinary retention or symptomatic non-stable prostate hypertrophy.
- 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.
- Patient has known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C infection.
- 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.
- Patient has known narrow-angle glaucoma.
- 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.
- Note: If a patient tests positive to any drugs of abuse tests, which cannot be explained by use of prescription medication, he/she will be excluded from the study. Unit=1 glass of wine (125 mL)=1 measure of spirits=½ pint of beer.
- 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.
- Patient has received a live attenuated vaccination within 30 days prior to Screening.
- Note: Inactivated influenza vaccination, pneumococcal vaccination, or any other inactivated vaccine is acceptable provided it is not administered within 7 days prior to Screening or randomisation (Visit 3).
- Patient who, in the opinion of the Investigator, is unable to abstain from protocol-defined prohibited medications during the study.
- 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.
- Note: Patient participation in observational studies (ie, studies that do not require change to medication or an additional intervention) is not exclusionary.
- Previous participation or prior screen failure in the present study.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- Patient has changed their smoking status (ie, restarted or stopped smoking) or initiation of a smoking cessation program within 6 weeks of Screening.
- Patient has participated in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Screening or who will enter the acute phase of a pulmonary rehabilitation program during the study. A patient in the maintenance phase of a pulmonary rehabilitation program is not to be excluded.
- Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. Inability to comply with requirements includes having an e-Diary completion rate of <70% during the run-in period.
- Patient who have donated or lost >500 mL of blood and/or plasma within the previous 3 months prior to Screening.
- Vulnerable patients (who has been placed in an institution due to a regulatory or court order).
Trial locations and contacts
5 sites in 2 countries.
5 sites in 2 countries
Germany3 sites
Research Site
Berlin, 14050
Research Site
Grosshansdof, 22927
Research Site
Wiesbaden, 65187
United Kingdom2 sites
Research Site
London, HA1 3UJ
Research Site
Manchester, M23 9QZ
About this study
Official title: A Phase IIa, Randomised, Multi-centre, Double-blind, Placebo and Active-controlled, 3 Periods, Crossover Study to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of Inhaled AZD8871 Administered Once Daily for 2 Weeks in Patients With Moderate to Severe COPD
This study will evaluate the efficacy and safety data of AZD8871 in patients with moderate to severe chronic obstructive pulmonary disease (COPD). This study will determine the 24-hour efficacy (lung function) profile of AZD8871 600 μg relative to placebo dry powder inhaler (DPI) based on trough forced expiratory volume in 1 second (FEV1) following repeated dosing (2 weeks). Anoro® Ellipta® (umeclidinium/vilanterol) once daily is included as an active control. This study aims at providing a novel approach to the treatment of COPD with greater efficacy than single-mechanism bronchodilators, equivalent to long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) administered as free- or fixed-dose combination therapies, with an equivalent or superior safety and tolerability profile.
Read the detailed description
This randomized, double-blind, placebo and active-controlled crossover study will be conducted at 5 sites in Germany and the United Kingdom (UK). Approximately 180 patients will be screened in order to randomize 72 patients into the study. Based on previous studies estimate, it is anticipated that 54 patients will be evaluable (study completers) assuming an approximate 25% dropout rate. A subset of 36 patients, who will have specifically consented for pharmacokinetics (PK), will undergo PK assessments. The study will consist of -
- A Screening period: Will last up to 28 days and consists of 2 Screening visits (Visit 1 and Visit 2) and a run-in period (between a minimum of 14 and a maximum of 28 days; from Visit 2 to Visit 3).
- Three treatment periods (Visit 3; 14 days each; each separated by a wash-out period of 42 to 49 days) and
- A Follow-up Visit: 42 days (up to 49 days) after last investigational product (IP) administration.
Patients will be requested to stop their usual COPD therapy after signing the informed consent form (ICF) at Visit 1 and will be maintained on a mono-component inhaled corticosteroid (ICS) therapy, if required. Patients that were taking any LAMA will be maintained with ipratropium (34 µg × 2 puffs 4 times per day) between Visit 1 and Visit 2. In addition, salbutamol 100 µg will be provided as rescue medication during the study as needed (rescue medication has to be discontinued 6 hours before any pulmonary function test). Visit 1 and Visit 2 could be performed on the same day if no wash-out of prior medication is required and the patient visits the site in fasting condition. In case any wash-out of prior medication is required, then Visit 2 will be performed after the wash-out is complete. If reversibility criteria and forced expiratory volume in 1 second (FEV1) predicted values are fulfilled according to inclusion criteria, the patient will be started on run-in period to assess clinical stability. If reversibility criteria or FEV1 predicted values are not met, pulmonary function tests could be rescheduled at the latest, up to Day 14. During the run in period, all patients will receive ipratropium 34 µg × 2 puffs 4 times per day (must be discontinued 8 hours prior to previous any pulmonary function test). A paper diary will be used to collect adverse events (AEs) and concomitant medication during run-in and wash-out periods.
Eligible patients will be randomized in 1:1:1:1:1:1 ratio to 1 of 6 treatment sequences and will receive orally 1 of the following 3 treatments sequence in the form of inhalation powder using DPI :
- AZD8871 600 µg once daily (double-blind).
- Anoro® Ellipta® (55 µg umeclidinium [UMEC]/ 22 µg vilanterol [VI]) once daily (double-blind).
- Placebo (double-blind). Study treatment administration during all the visits at the sites (Day 1, Day 2, Day 8, and Day 14 of each treatment period) will be supervised by study personnel.
During the treatment period Visits, safety and tolerability assessments and pulmonary function measurements will be taken pre-dose and up to 24 hours (Day 1) and up to 4 hours (Day 8) post-dose, respectively.
At Visits 3 to 11, a subset of 36 patients will undergo PK assessments. Blood samples will be collected pre-dose and up to 24 hours post dose.
In follow-up visit, AEs, safety laboratory, electrocardiogram (ECG), vital signs and physical examination will be assessed.
The study includes 12 visits and the entire study period is scheduled to take from a minimum of 6.5 months (182 days) to a maximum of 7.5 months (217 days) for each individual patient. The estimated study duration is 12 months.
- Conditions
- Chronic Obstructive Pulmonary Disease
- Being tested
- AZD8871, Anoro® Ellipta®
- Keywords
- Moderate to severe COPD, Muscarinic receptor antagonist, β2 adrenoceptor agonist (MABA), Long-acting muscarinic antagonist (LAMA), Long-acting β2-agonist (LABA), Inhaled long-acting bronchodilator, Small airways disease (obstructive bronchiolitis), Parenchymal destruction (emphysema),
- Medical subject headings
- Pulmonary Disease, Chronic Obstructive, Emphysema
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD8871Drug
Randomized patients will receive 14 repeated daily doses of AZD8871 600 µg inhalation powder via DPI.
Anoro® Ellipta®Drug
Also called Anoro® - Umeclidinium/Vilanterol, Ellipta® - Device
Randomized patients will receive 14 repeated daily doses of Anoro® Ellipta® (55 µg/22 µg) inhalation powder via DPI.
| Study group | Role | What they receive |
|---|---|---|
| Treatment sequence A | Experimental | Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow:
Treatment period 1: AZD8871 600 µg and Anoro® Ellipta® matching placebo.
Treatment period 2: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg.
Treatment period 3: Matching placebo of AZD8871 and Anoro® Ellipta® Receives: Drug: AZD8871; Drug: Anoro® Ellipta® |
| Treatment sequence B | Experimental | Randomized patients will receive multiple oral dose of inhalation powder via DPI as follows:
Treatment period 1: AZD8871 600 µg and Anoro® Ellipta® matching placebo.
Treatment period 2: Matching placebo of AZD8871 and Anoro® Ellipta®
Treatment period 3: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. Receives: Drug: AZD8871; Drug: Anoro® Ellipta® |
| Treatment sequence C | Experimental | Randomized patients will receive multiple oral dose of inhalation powder via DPI as follows:
Treatment period 1: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg.
Treatment period 2: AZD8871 600 µg and Anoro® Ellipta® matching placebo.
Treatment period 3: Matching placebo of AZD8871 and Anoro® Ellipta® Receives: Drug: AZD8871; Drug: Anoro® Ellipta® |
| Treatment sequence D | Experimental | Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow:
Treatment period 1: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg.
Treatment period 2: Matching placebo of AZD8871 and Anoro® Ellipta®
Treatment period 3: AZD8871 600 µg and Anoro® Ellipta® matching placebo. Receives: Drug: AZD8871; Drug: Anoro® Ellipta® |
| Treatment sequence E | Experimental | Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow:
Treatment period 1: Matching placebo of AZD8871 and Anoro® Ellipta®
Treatment period 2: AZD8871 600 µg and Anoro® Ellipta® matching placebo.
Treatment period 3: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. Receives: Drug: AZD8871; Drug: Anoro® Ellipta® |
| Treatment sequence F | Experimental | Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow:
Treatment period 1: Matching placebo of AZD8871 and Anoro® Ellipta®
Treatment period 2: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg.
Treatment period 3: AZD8871 600 µg and Anoro® Ellipta® matching placebo. Receives: Drug: AZD8871; Drug: Anoro® Ellipta® |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline in Trough FEV1 at Day 15
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
Measured: Day 15
Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) at Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD. At each visit, patients are asked to evaluate the impact of COPD on their wellbeing and daily life on a 6-point Likert scale ranging from 0 to 5, with higher scores indicating a higher impact of COPD. The CAT is expressed as a total score, which is a sum of the 8 questions, ranging from 0 to 40.
Measured: Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
Secondary outcomes (18)
FEV1 AUC(0-4)/4h (Area Under the Curve for the Change in FEV1 From Baseline to 4h, Normalised by the Time Window)
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Measured: At Day 1, Day 8, and Day 14
FEV1 AUC(0-8)/8h (Area Under the Curve for the Change in FEV1 From Baseline to 8h, Normalised by the Time Window)
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Measured: Day 1 and Day 14
FEV1 AUC(0-12)/12h (Area Under the Curve for the Change in FEV1 From Baseline to 12h, Normalised by the Time Window)
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Measured: Day 1 and Day 14
FEV1 AUC(0-24)/24h (Area Under the Curve for the Change in FEV1 From Baseline to 24h, Normalised by the Time Window)
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Measured: Day 1 and Day 14
Change From Baseline in Trough FEV1 on Day 2 and Day 8.
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Measured: Day 2 and Day 8.
Change From Baseline in Peak FEV1 on Day 1, Day 8 and Day 14.
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Measured: At Day 1, Day 8, and Day 14.
Change From Baseline in Breathlessness, Cough and Sputum Scale (BCSS) Total Score at Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD. The BCSS questionnaire is a 3-item, patient-reported outcome (PRO) measure. On a daily basis, patients are asked to evaluate each of their 3 symptoms (breathlessness, cough, and sputum) on a 5-point Likert scale ranging from 0 to 4, with higher scores indicating a higher severity of the symptom. The BCSS questionnaire is expressed as a daily total score, which is the sum of the 3 symptom scores, ranging from 0 to 12.
Measured: Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
Number of Participants With Adverse Events.
To evaluate the safety and tolerability of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Measured: From Screening to folow-up or discontinuation (42 days after last study drug)
Maximum Plasma Concentration (Cmax)
To investigate the Cmax of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Measured: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Time to Reach Maximum Plasma Concentration (Tmax)
To investigate the Tmax of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Measured: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Time to Reach Last Quantifiable Plasma Concentration (Tlast)
To investigate the Tlast of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Measured: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Area Under the Plasma Concentration-curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast)
To investigate the AUClast of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Measured: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Area Under the Plasma Concentration-curve From Time 0 to 24 Hours Post-dose [AUC(0-24)]
To investigate the AUC(0-24) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Measured: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Average Plasma Concentration During a Dosing Interval (Cavg)
To investigate the Cavg of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Measured: At Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Fluctuation Index During a Dosing Interval (%Fluctuation)
To investigate the %Fluctuation of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD. Fluctuation index during a dosing interval is estimated as 100*(Cmax - Cmin)/Cavg (%), where Cmin is the minimum concentration at the end of the dosing interval.
Measured: At Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Accumulation Ratio for Cmax (Rac(Cmax))
To investigate the Rac (Cmax) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD. Accumulation ratio for Cmax estimated as (Cmax on Day 14/Cmax on Day 1).
Measured: At Day 14
Accumulation Ratio for AUC(0-24) Rac(AUC(0-24))
To investigate the Rac(AUC(0-24) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD. Accumulation ratio for AUC0-24 estimated as (AUC0-24 on Day 14/AUC0-24 on Day 1).
Measured: At Day 14
Change From Baseline in Use of Rescue Medication
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Measured: Day 1 to Day 8 and Day 9 to Day 14
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2018
- Study start10 Oct 2018
- Primary completion7 Aug 2019
- Study completion7 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Obstructive Pulmonary DiseaseStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 73 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Parexel
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03645434
- Sponsor's protocol ID
- D6640C00006
- Status last verified
- Nov 2020
- First submitted
- 9 Aug 2018
- Last updated
- 17 Dec 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Singh D, Beier J, Astbury C, Belvisi MG, Da Silva CA, Jauhiainen A, Jimenez E, Lei A, Necander S, Smith JA, Wahlby Hamren U, Xin W, Psallidas I. The novel bronchodilator navafenterol: a phase 2a, multicentre, randomised, double-blind, placebo-controlled crossover trial in COPD. Eur Respir J. 2022 Apr 7;59(4):2100972. doi: 10.1183/13993003.00972-2021. Print 2022 Apr.
PubMed 34503985
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase IIa, Randomised, Multi-centre, Double-blind, Placebo and Active-controlled, 3 Periods, Crossover Study to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of Inhaled AZD8871 Administered Once Daily for 2 Weeks in Patients With Moderate to Severe COPD
- ClinicalTrials.gov ID
- NCT03645434
- Acronym / sponsor ID
- D6640C00006
- Conditions
- Chronic Obstructive Pulmonary Disease
- Keywords
- Moderate to severe COPD, Muscarinic receptor antagonist, β2 adrenoceptor agonist (MABA), Long-acting muscarinic antagonist (LAMA), Long-acting β2-agonist (LABA), Inhaled long-acting bronchodilator, Small airways disease (obstructive bronchiolitis), Parenchymal destruction (emphysema),
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 73 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Collaborators
- Parexel
- Study start
- 10 Oct 2018 (actual)
- Primary completion
- 7 Aug 2019 (actual)
- Study completion
- 7 Aug 2019 (actual)
- First posted
- 24 Aug 2018 (actual)
- Results
- Posted 17 Dec 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will evaluate the efficacy and safety data of AZD8871 in patients with moderate to severe chronic obstructive pulmonary disease (COPD). This study will determine the 24-hour efficacy (lung function) profile of AZD8871 600 μg relative to placebo dry powder inhaler (DPI) based on trough forced expiratory volume in 1 second (FEV1) following repeated dosing (2 weeks). Anoro® Ellipta® (umeclidinium/vilanterol) once daily is included as an active control. This study aims at providing a novel approach to the treatment of COPD with greater efficacy than single-mechanism bronchodilators, equivalent to long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) administered as free- or fixed-dose combination therapies, with an equivalent or superior safety and tolerability profile.
Detailed description
This randomized, double-blind, placebo and active-controlled crossover study will be conducted at 5 sites in Germany and the United Kingdom (UK). Approximately 180 patients will be screened in order to randomize 72 patients into the study. Based on previous studies estimate, it is anticipated that 54 patients will be evaluable (study completers) assuming an approximate 25% dropout rate. A subset of 36 patients, who will have specifically consented for pharmacokinetics (PK), will undergo PK assessments. The study will consist of -
- A Screening period: Will last up to 28 days and consists of 2 Screening visits (Visit 1 and Visit 2) and a run-in period (between a minimum of 14 and a maximum of 28 days; from Visit 2 to Visit 3).
- Three treatment periods (Visit 3; 14 days each; each separated by a wash-out period of 42 to 49 days) and
- A Follow-up Visit: 42 days (up to 49 days) after last investigational product (IP) administration.
Patients will be requested to stop their usual COPD therapy after signing the informed consent form (ICF) at Visit 1 and will be maintained on a mono-component inhaled corticosteroid (ICS) therapy, if required. Patients that were taking any LAMA will be maintained with ipratropium (34 µg × 2 puffs 4 times per day) between Visit 1 and Visit 2. In addition, salbutamol 100 µg will be provided as rescue medication during the study as needed (rescue medication has to be discontinued 6 hours before any pulmonary function test). Visit 1 and Visit 2 could be performed on the same day if no wash-out of prior medication is required and the patient visits the site in fasting condition. In case any wash-out of prior medication is required, then Visit 2 will be performed after the wash-out is complete. If reversibility criteria and forced expiratory volume in 1 second (FEV1) predicted values are fulfilled according to inclusion criteria, the patient will be started on run-in period to assess clinical stability. If reversibility criteria or FEV1 predicted values are not met, pulmonary function tests could be rescheduled at the latest, up to Day 14. During the run in period, all patients will receive ipratropium 34 µg × 2 puffs 4 times per day (must be discontinued 8 hours prior to previous any pulmonary function test). A paper diary will be used to collect adverse events (AEs) and concomitant medication during run-in and wash-out periods.
Eligible patients will be randomized in 1:1:1:1:1:1 ratio to 1 of 6 treatment sequences and will receive orally 1 of the following 3 treatments sequence in the form of inhalation powder using DPI :
- AZD8871 600 µg once daily (double-blind).
- Anoro® Ellipta® (55 µg umeclidinium [UMEC]/ 22 µg vilanterol [VI]) once daily (double-blind).
- Placebo (double-blind). Study treatment administration during all the visits at the sites (Day 1, Day 2, Day 8, and Day 14 of each treatment period) will be supervised by study personnel.
During the treatment period Visits, safety and tolerability assessments and pulmonary function measurements will be taken pre-dose and up to 24 hours (Day 1) and up to 4 hours (Day 8) post-dose, respectively.
At Visits 3 to 11, a subset of 36 patients will undergo PK assessments. Blood samples will be collected pre-dose and up to 24 hours post dose.
In follow-up visit, AEs, safety laboratory, electrocardiogram (ECG), vital signs and physical examination will be assessed.
The study includes 12 visits and the entire study period is scheduled to take from a minimum of 6.5 months (182 days) to a maximum of 7.5 months (217 days) for each individual patient. The estimated study duration is 12 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Treatment sequence A | Experimental | Drug: AZD8871, Drug: Anoro® Ellipta®Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow: Treatment period 1: AZD8871 600 µg and Anoro® Ellipta® matching placebo. Treatment period 2: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. Treatment period 3: Matching placebo of AZD8871 and Anoro® Ellipta® |
| Treatment sequence B | Experimental | Drug: AZD8871, Drug: Anoro® Ellipta®Randomized patients will receive multiple oral dose of inhalation powder via DPI as follows: Treatment period 1: AZD8871 600 µg and Anoro® Ellipta® matching placebo. Treatment period 2: Matching placebo of AZD8871 and Anoro® Ellipta® Treatment period 3: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. |
| Treatment sequence C | Experimental | Drug: AZD8871, Drug: Anoro® Ellipta®Randomized patients will receive multiple oral dose of inhalation powder via DPI as follows: Treatment period 1: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. Treatment period 2: AZD8871 600 µg and Anoro® Ellipta® matching placebo. Treatment period 3: Matching placebo of AZD8871 and Anoro® Ellipta® |
| Treatment sequence D | Experimental | Drug: AZD8871, Drug: Anoro® Ellipta®Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow: Treatment period 1: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. Treatment period 2: Matching placebo of AZD8871 and Anoro® Ellipta® Treatment period 3: AZD8871 600 µg and Anoro® Ellipta® matching placebo. |
| Treatment sequence E | Experimental | Drug: AZD8871, Drug: Anoro® Ellipta®Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow: Treatment period 1: Matching placebo of AZD8871 and Anoro® Ellipta® Treatment period 2: AZD8871 600 µg and Anoro® Ellipta® matching placebo. Treatment period 3: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. |
| Treatment sequence F | Experimental | Drug: AZD8871, Drug: Anoro® Ellipta®Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow: Treatment period 1: Matching placebo of AZD8871 and Anoro® Ellipta® Treatment period 2: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. Treatment period 3: AZD8871 600 µg and Anoro® Ellipta® matching placebo. |
Who may qualify
- Ages
- 40 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Provision of signed and dated, written ICF prior to any study-specific procedures, sampling, and analyses.
- Patient must be 40 to 85 years male and/or females of non-childbearing potential who are not pregnant/lactating at the time of signing the ICF (Screening; Visit 1).
- Patient with an established clinical history of moderate to severe COPD for more than 1 year at Screening, according to the GOLD COPD guidelines.
- Patient who is a current or former smoker (defined as one who has stopped smoking for at least 6 months prior to Screening) 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)].
- 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.
Key exclusion criteria (40 listed)
- 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.
- Patient has alpha-1 antitrypsin deficiency as the cause of COPD.
- 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.
- 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).
- 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. Note: A patient using continuous positive airway pressure or bi level positive airway pressure for Sleep Apnoea Syndrome is allowed in the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AZD8871Randomized patients will receive 14 repeated daily doses of AZD8871 600 µg inhalation powder via DPI. | Drug | Treatment sequence A, Treatment sequence B, Treatment sequence C, Treatment sequence D, Treatment sequence E, Treatment sequence F |
| Anoro® Ellipta®Also: Anoro® - Umeclidinium/Vilanterol, Ellipta® - DeviceRandomized patients will receive 14 repeated daily doses of Anoro® Ellipta® (55 µg/22 µg) inhalation powder via DPI. | Drug | Treatment sequence A, Treatment sequence B, Treatment sequence C, Treatment sequence D, Treatment sequence E, Treatment sequence F |
Primary outcome
Change From Baseline in Trough FEV1 at Day 15
Time frame: Day 15
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) at Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
Time frame: Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD. At each visit, patients are asked to evaluate the impact of COPD on their wellbeing and daily life on a 6-point Likert scale ranging from 0 to 5, with higher scores indicating a higher impact of COPD. The CAT is expressed as a total score, which is a sum of the 8 questions, ranging from 0 to 40.
18 secondary outcomes
FEV1 AUC(0-4)/4h (Area Under the Curve for the Change in FEV1 From Baseline to 4h, Normalised by the Time Window)
Time frame: At Day 1, Day 8, and Day 14
FEV1 AUC(0-8)/8h (Area Under the Curve for the Change in FEV1 From Baseline to 8h, Normalised by the Time Window)
Time frame: Day 1 and Day 14
FEV1 AUC(0-12)/12h (Area Under the Curve for the Change in FEV1 From Baseline to 12h, Normalised by the Time Window)
Time frame: Day 1 and Day 14
FEV1 AUC(0-24)/24h (Area Under the Curve for the Change in FEV1 From Baseline to 24h, Normalised by the Time Window)
Time frame: Day 1 and Day 14
Change From Baseline in Trough FEV1 on Day 2 and Day 8.
Time frame: Day 2 and Day 8.
Change From Baseline in Peak FEV1 on Day 1, Day 8 and Day 14.
Time frame: At Day 1, Day 8, and Day 14.
Change From Baseline in Breathlessness, Cough and Sputum Scale (BCSS) Total Score at Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
Time frame: Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
Number of Participants With Adverse Events.
Time frame: From Screening to folow-up or discontinuation (42 days after last study drug)
Maximum Plasma Concentration (Cmax)
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Time to Reach Maximum Plasma Concentration (Tmax)
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Time to Reach Last Quantifiable Plasma Concentration (Tlast)
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Area Under the Plasma Concentration-curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast)
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Area Under the Plasma Concentration-curve From Time 0 to 24 Hours Post-dose [AUC(0-24)]
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Average Plasma Concentration During a Dosing Interval (Cavg)
Time frame: At Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Fluctuation Index During a Dosing Interval (%Fluctuation)
Time frame: At Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Accumulation Ratio for Cmax (Rac(Cmax))
Time frame: At Day 14
Accumulation Ratio for AUC(0-24) Rac(AUC(0-24))
Time frame: At Day 14
Change From Baseline in Use of Rescue Medication
Time frame: Day 1 to Day 8 and Day 9 to Day 14
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Dec 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34503985Singh D, Beier J, Astbury C, Belvisi MG, Da Silva CA, Jauhiainen A, Jimenez E, Lei A, Necander S, Smith JA, Wahlby Hamren U, Xin W, Psallidas I. The novel bronchodilator navafenterol: a phase 2a, multicentre, randomised, double-blind, placebo-controlled crossover trial in COPD. Eur Respir J. 2022 Apr 7;59(4):2100972. doi: 10.1183/13993003.00972-2021. Print 2022 Apr.
- Redacted SAP.Link provided by the sponsor.
- Redacted CSP.Link provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
5 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing AZD8871 and Anoro® Ellipta® in people with Chronic Obstructive Pulmonary Disease, run by AstraZeneca at 5 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Germany, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline in Trough FEV1 at Day 15 (time frame: Day 15). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03645434, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2020.