Two-part Safety, Tolerability, Pharmacodynamic and -Kinetic Study of Inhaled AZD8871 in Asthmatic and COPD Subjects

A 2-part, Randomised, Placebo-controlled, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of AZD8871 Delivered by Inhalation in Asthmatic and Chronic Obstructive Pulmonary Disease (COPD) Subjects

This is a phase I, randomised, placebo-controlled 2-part study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8871 delivered by inhalation, in asthmatic and chronic obstructive pulmonary disease (COPD) subjects.

Study Overview

• Status: Completed
• Conditions: Asthma (Part 1); COPD (Part 2)
• Intervention / Treatment: Drug: Dose 1, AZD8871 50 μg (Part 1); Drug: Dose 3, AZD8871 300 μg (Part 1); Drug: Dose 5, AZD8871 1200 µg (Part 1); Drug: Placebo, AZD8871 placebo (Part 1); Drug: Dose 2, AZD8871 100 μg (Part 1); Drug: Dose 4, AZD8871 600 µg (Part 1); Drug: Dose 6, AZD8871 1800 μg (Part 1); Drug: Treatment A, AZD8871 dose A (Part 2); Drug: Treatment B, AZD8871 dose B (Part 2); Drug: Treatment C, Indacaterol 150 μg (Part 2); Drug: Treatment D, Tiotropium 18 μg (Part 2)

Detailed Description

This study is an integrated Phase I protocol divided into 2 parts.

Part 1: single ascending dose study (6 AZD8871 dose levels) in 16 male subjects with mild asthma. AZD8871 will be administered (by the Genuair® inhaler) under supervision at the study centre, according to the randomisation scheme

Part 2: a 5 treatment period single dose study (of AZD8871 [two doses], indacaterol, tiotropium and placebo) in 40 male and non-childbearing female subjects with moderate to severe COPD. Each treatment period will be separated by a washout period of at least 7 days. The primary comparison for bronchodilation will be between AZD8871 doses and placebo.

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Harrow, United Kingdom
    • Research Site
  • Manchester, United Kingdom
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:Part 1

1. Subjects who are able and willing to provide written informed consent prior to conducting any study-related procedures, including withdrawal of medications
2. Adult male subjects aged 18 to 70 years (both inclusive)
3. Body mass index (BMI) from 18 to 32 kg/m2 at screening
4. Clinical diagnosis of asthma (according to the Global Initiative for Asthma [GINA] guidelines) for at least 6 months prior to screening
5. Ability to change current asthma therapy, to discontinue previous prescribed medications after signature of informed consent as per required washout periods
6. Screening FEV1 value of ≥70% of the predicted normal value
7. FEV1 reversibility of ≥12% and an absolute increase of at least 200 mL over the baseline value within 30 min after inhalation of 400 µg (4 puffs) of salbutamol via a metered dose inhaler, with spacer device
8. Subjects using intermittent salbutamol and / or subjects on a stable dose of low dose Inhaled corticosteroid (as defined by the GINA guidelines) at least 4 weeks prior to screening
9. Predose FEV1 value of first treatment period within the range of ± 20% of the FEV1 measured at screening prior to salbutamol inhalation
10. No current smokers, no subjects with a smoking history during the last 12 months and no subjects with a total smoking history of more than 10 pack-years
11. No other relevant pulmonary disease or history of thoracic surgery
12. Subjects who are otherwise healthy as determined by medical history, physical examination, 12-lead ECG findings
13. Normal blood pressure (defined as Systolic blood pressure [SBP] between 100 and 140 mmHg for subjects ≤59 years of age and between 100 and 150 mmHg for subjects ≥60 years of age, and Diastolic blood pressure [DBP] between 40 and 90 mmHg) at screening
14. Subjects whose clinical laboratory test results are not clinically relevant and are acceptable to the Investigator.
15. Subjects who are negative for hepatitis B surface antigen (HBsAg), hepatitis B core (HBc) antibody (IgM), hepatitis C antibody and human immunodeficiency virus (HIV) I and II antibodies at screening
16. Subjects who are negative for drugs of abuse and alcohol tests at screening and admission
17. Subjects able to perform repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS) / European Respiratory Society (ERS) 2005(9) criteria at screening

Inclusion Criteria: Part 2

1. Adult male and non-childbearing female subjects aged ≥40 years with a clinical diagnosis of stable moderate to severe COPD according to GOLD guidelines at screening
2. Females must be of non-childbearing potential, confirmed at screening by fulfilling study predefined criteria
3. Post-salbutamol FEV1 <80% and ≥30% of the predicted normal value and post-salbutamol FEV1 / forced vital capacity (FVC) <70%
4. BMI < 40 kg/m2 at screening
5. Ability to change current COPD therapy, to discontinue previous prescribed medications after signature of informed consent as per required washout periods
6. Current or ex-smokers with a smoking history of ≥10 pack years
7. No evidence of clinically significant respiratory and / or cardiovascular conditions (e.g. uncontrolled hypertension) or laboratory abnormalities
8. No other relevant pulmonary disease or history of thoracic surgery
9. Subjects who are negative for HBsAg, HBc IgM, hepatitis C antibody and HIV I and II antibodies at screening
10. Subjects who are able and willing to provide written informed consent prior to conducting any study-related procedures, including withdrawal of medications
11. Medical history must be verified by either a personal physician or medical practitioner as appropriate
12. Subjects able to perform repeatable pulmonary function testing for FEV1 according to the ATS / ERS 2005(9) criteria at screening

Exclusion Criteria (Part 1 & 2):

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
2. Previous enrolment or randomisation of treatment in the present study
3. Current evidence or recent history of any clinically significant and unstable disease (other than asthma/COPD) or abnormality that could put the subject at risk or could confound the results of the study
4. Subjects with a surgical history clinically relevant for the purpose of the study
5. 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
6. Subjects with serious adverse reaction or serious hypersensitivity to Tiotropium (for Part 2 only), Indacaterol (for Part 2 only), or the formulation excipients (eg, lactose) or other drugs in the same pharmacologic class (for Part 1 and Part 2)
7. Current diagnosis of COPD (for Part 1 only) or history of / or current diagnosis for asthma (for Part 2 only)
8. Recent history of asthma / COPD exacerbation requiring hospitalisation or need for increased maintenance treatments for asthma / COPD within 6 weeks prior to screening or prior to randomisation
9. Use of daily oxygen therapy >10 h per day (for Part 2 only)
10. Use of systemic steroids for respiratory reasons within 6 weeks prior to screening
11. Lower respiratory tract infection within 6 weeks prior to screening or prior to randomisation
12. Upper respiratory tract infection requiring antibiotics within 6 weeks prior to screening or prior to randomisation
13. Current history of tuberculosis, bronchiectasis or other non-specific pulmonary disease
14. Subject with significant cardiovascular disease that may be vulnerable to cardiovascular instability
15. QTcF (QT interval corrected, Fridericia formula QT[msec]/RR[s]) interval, >450 ms for males and >470 ms for females at screening or prior to randomisation, or history of long QT syndrome
16. PR (duration in milliseconds from the beginning of wave P to onset of ventricular depolarisation [Q or R]) interval >200 ms at screening or prior to randomisation (for Part 1 only) Note: 4- 6 hours of ECG rhythm monitoring with telemetry will be performed on Day-1 to identify patients that may have any clinical significant abnormality prior to randomisation. If this occurs, patients should not participate in the study
17. Subjects with serum potassium concentration < 3.5mmol/l at screening
18. Subjects with a history of excessive use or abuse of alcohol within the past 2 years
19. Subjects with a history of drug abuse within the past 2 years
20. Subjects who are positive for drugs of abuse and alcohol tests at screening and prior to randomisation. Subjects consuming more than 14 (female subjects) or 21 (male subjects) units of alcohol a week
21. Donation or loss >400 ml of blood and plasma within the previous 3 months prior to screening
22. Subjects with a significant infection or known inflammatory process at screening or prior to randomisation
23. Subjects with acute gastrointestinal symptoms at the time of screening or prior to randomisation (eg, nausea, vomiting, diarrhoea, heartburn)
24. Subjects with an acute infection such as influenza at the time of screening or prior to randomisation
25. Male subjects who do not agree to follow instructions to avoid pregnancies
26. Subjects who are not able to adhere to the restrictions on prior and concomitant medications
27. Subjects who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required washout period for a particular prohibited medication
28. Subjects who have used any investigational drug within 3 months prior to screening or within the equivalent time of 6 half-lives of receiving the last administration, whichever is longer
29. Subjects who have received the last dose of investigational product more than 3 months ago but who are on an extended follow-up
30. Subjects who are unlikely to co-operate with the requirements of the study, or the study center or the subjects who are unwilling or unable to follow the instructions of the principal investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

18

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1, Part 1; Period 1: Dose 1 Period 2: Dose 3 Period 3: Dose 5	Drug: Dose 1, AZD8871 50 μg (Part 1); 50 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 3, AZD8871 300 μg (Part 1); 300 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 5, AZD8871 1200 µg (Part 1); 1200 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 2, Part 1; Period 1: Placebo Period 2: Dose 3 Period 3: Dose 5	Drug: Dose 3, AZD8871 300 μg (Part 1); 300 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 5, AZD8871 1200 µg (Part 1); 1200 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Placebo, AZD8871 placebo (Part 1); AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 3, Part 1; Period 1: Dose 1 Period 2: Placebo Period 3: Dose 5	Drug: Dose 1, AZD8871 50 μg (Part 1); 50 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 5, AZD8871 1200 µg (Part 1); 1200 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Placebo, AZD8871 placebo (Part 1); AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 4, Part 1; Period 1: Dose 1 Period 2: Dose 3 Period 3: Placebo	Drug: Dose 1, AZD8871 50 μg (Part 1); 50 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 3, AZD8871 300 μg (Part 1); 300 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Placebo, AZD8871 placebo (Part 1); AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 5, Part 1; Period 1: Dose 2 Period 2: Dose 4 Period 3: Dose 6	Drug: Dose 2, AZD8871 100 μg (Part 1); 100 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 4, AZD8871 600 µg (Part 1); 600 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 6, AZD8871 1800 μg (Part 1); 1800 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 6, Part 1; Period 1: Placebo Period 2: Dose 4 Period 3: Dose 6	Drug: Placebo, AZD8871 placebo (Part 1); AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 4, AZD8871 600 µg (Part 1); 600 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 6, AZD8871 1800 μg (Part 1); 1800 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 7, Part 1; Period 1: Dose 2 Period 2: Placebo Period 3: Dose 6	Drug: Placebo, AZD8871 placebo (Part 1); AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 2, AZD8871 100 μg (Part 1); 100 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 6, AZD8871 1800 μg (Part 1); 1800 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 8, Part 1; Period 1: Dose 2 Period 2: Dose 4 Period 3: Placebo	Drug: Placebo, AZD8871 placebo (Part 1); AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 2, AZD8871 100 μg (Part 1); 100 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Dose 4, AZD8871 600 µg (Part 1); 600 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 1, Part 2; Period 1: Treatment A Period 2: Treatment B Period 3: Treatment E Period 4: Treatment C Period 5: Treatment D	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 2, Part 2; Period 1: Treatment B Period 2: Treatment C Period 3: Treatment A Period 4: Treatment D Period 5: Treatment E	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 3, Part 2; Period 1: Treatment C Period 2: Treatment D Period 3: Treatment B Period 4: Treatment E Period 5: Treatment A	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 4, Part 2; Period 1: Treatment D Period 2: Treatment E Period 3: Treatment C Period 4: Treatment A Period 5: Treatment B	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 5, Part 2; Period 1: Treatment E Period 2: Treatment A Period 3: Treatment D Period 4: Treatment B Period 5: Treatment C	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 6, Part 2; Period 1: Treatment D Period 2: Treatment C Period 3: Treatment E Period 4: Treatment B Period 5: Treatment A	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 7, Part 2; Period 1: Treatment E Period 2: Treatment D Period 3: Treatment A Period 4: Treatment C Period 5: Treatment B	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 8, Part 2; Period 1: Treatment A Period 2: Treatment E Period 3: Treatment B Period 4: Treatment D Period 5: Treatment C	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 9, Part 2; Period 1: Treatment B Period 2: Treatment A Period 3: Treatment C Period 4: Treatment E Period 5: Treatment D	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 10, Part 2; Period 1: Treatment C Period 2: Treatment B Period 3: Treatment D Period 4: Treatment A Period 5: Treatment E	Drug: Treatment A, AZD8871 dose A (Part 2); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); Drug: Treatment B, AZD8871 dose B (Part 2); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); Drug: Treatment C, Indacaterol 150 μg (Part 2); 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule; Drug: Treatment D, Tiotropium 18 μg (Part 2); 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants With Mild Persistent Asthma (Part 1) and COPD (Part 2) With at Least 1 Treatment-emergent Adverse Event	An adverse event is the development of an undesirable medical condition, or the deterioration of a pre-existing medical condition, following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms, signs, or the abnormal results of laboratory parameters (haematology, blood chemistry, urinalysis, physical examination, 12-lead ECGs and telemetry, and vital signs). AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.	From the time of informed consent up to 14 (±2) days after the last dose of investigational product. Unresolved AEs were followed up by the investigator for as long as medically indicated.
Number of Participants With Clinically Relevant Abnormalities in Blood Pressure	Blood pressure (BP) measurements (diastolic [DBP] and systolic BP [SBP]) taken after ~5 minutes rest in supine position, at screening, baseline (≤1 hour before IP administration), 10 and 30 minutes, 1, 2, 3, 4, 8, 12 hours (Day 1) and 24 and 36 hours (Day 2) after IP administration. Normal BP at screening: SBP 100-140 mmHg (subjects aged ≤59 years) and 100-150 mmHg (subjects aged ≥60 years), and DBP 40-90 mmHg. Criteria for notable changes in BP: High SBP: (≥180 and increase over baseline (predose) ≥20) or (≥200 and baseline <200) Low SBP: (≤ 90 and decrease over baseline ≥20) or (≤75 and baseline >75) High DBP: (≥105 and increase over baseline ≥15) or (≥115 and baseline <115) Low DBP: (≤50 and decrease over baseline ≥15) or (≤40 and baseline >40) All out of range values were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until considered non-clinically relevant.	From the time of informed consent up to 36 hours after last dose of IP.
Number of Participants With Clinically Relevant Abnormalities in Electrocardiograms (HR, QTcF and Other ECG Parameters).	HR, QTcF and other ECG abnormalities were assessed by local digital 12-lead ECG performed in triplicate at the time points indicated: ECG (Parts 1 and 2) was assessed at Screening, Day 1 baseline, 10 min, 30 min, 1 hour (h), 2 h, 3 h, 4 h, 8 h, 12 h, 24 h, 36 h after dosing. Telemetry (Part 1), assessed with at least 2 lead real time display, was recorded at Day -1 (4-6 hours continuous recording, at the time this was more convenient for the logistics of the unit) and on Day 1 from the time of the IP administration up to at least 24 hours, but if advised by the Investigator or designee, then up to 36 hours after IP administration. Abnormal findings were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until the abnormality was considered non-clinically relevant.	From the time of informed consent up to 36 hours after last dose of IP.
Number of Participants With Clinically Relevant Abnormalities in Clinical Biochemistry, Hematology and Urinalysis	A composite of clinically relevant abnormalities in clinical biochemistry, hematology and urinalysis laboratory evaluations. Laboratory tests (haematology, blood chemistry, and urinalysis) were performed at screening, at Day -1 (Part 1 only), at 24 hours (Day 2) and at follow-up (7 [±2] days) after IP administration. Coagulation was only performed at screening; TSH, T4 only at screening, at Day-1 and at follow-up. Abnormal findings were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until the abnormality was considered non-clinically relevant.	From the time of informed consent up to 7 days after the last dose of IP.
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) on Day 2	Pharmacodynamics of AZD8871 before (-45 min and -15 min pre-dose) and after single dosing of AZD8871 Forced expiratory volume in 1 second (FEV1) on Day 2 (defined as the average of the values 23:00 and 24:00 hours after the morning dose of investigational product)	Baseline (Day 1) to 36 hours post-dose (Day 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of AZD8871 in Parts 1 and 2	Cmax (maximum observed plasma drug concentrations) of AZD8871 on Day 1 of each treatment period.	Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
Tmax of AZD8871 in Parts 1 and 2	tmax (time to reach maximum concentration) of AZD8871 on Day 1 of each treatment period.	Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
AUC(0-t) of AZD8871 in Parts 1 and 2	AUC(0-t) (area under the concentration-time curve from time zero to time of the last quantifiable measurable concentration) of AZD8871 on Day 1 of each treatment period.	Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
AUC(0-24) of AZD8871 in Parts 1 and 2	AUC(0-24) (area under the concentration-time curve from zero to 24h) of AZD8871 on Day 1 of each treatment period.	Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC of AZD8871 in Parts 1 and 2	AUC (area under the concentration-time curve from time 0 to infinity) of AZD8871 on Day 1 of each treatment period	Predose, and 5 min, 15 min, 30 min, and 45 min, at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h and 36 h (Day 2) post-dose
Elimination Half-life of AZD8871 in Parts 1 and 2	Elimination half-life (t½λz) for AZD8871 on Day 1 of each treatment period. t½λz was generally calculated over a period of less than 3 times the resultant half-life	Predose, and 5 min, 15 min, 30 min, and 45 min, at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h and 36 h (Day 2) post-dose

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Muna Albayaty, MBChB, MSc,MFPM, PAREXEL Early Phase Clinical Unit, London, United Kingdom; Principal Investigator: Dave Singh, Prof., The Medicines Evaluation Unit (MEU), Manchester, United Kingdom

Publications and helpful links

General Publications

• Jimenez E, Astbury C, Albayaty M, Wahlby-Hamren U, Seoane B, Villarroel C, Pujol H, Bermejo MJ, Aggarwal A, Psallidas I. Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator. Respir Res. 2020 Sep 9;21(Suppl 1):211. doi: 10.1186/s12931-020-01470-5.
• Singh D, Balaguer V, Astbury C, Wahlby-Hamren U, Jimenez E, Seoane B, Villarroel C, Lei A, Aggarwal A, Psallidas I. Navafenterol (AZD8871) in patients with COPD: a randomized, double-blind, phase I study evaluating safety and pharmacodynamics of single doses of this novel, inhaled, long-acting, dual-pharmacology bronchodilator. Respir Res. 2020 Sep 9;21(Suppl 1):102. doi: 10.1186/s12931-020-01347-7.

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: October 8, 2015
• First Submitted That Met QC Criteria: October 8, 2015
• First Posted (Estimate): October 9, 2015

Study Record Updates

• Last Update Posted (Actual): November 8, 2018
• Last Update Submitted That Met QC Criteria: April 6, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Tolerability; Pharmacodynamics; AZD8871; mild persistent asthma; moderate to severe COPD
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide
• Other Study ID Numbers: D6640C00001; 2015-002906-36 (EudraCT Number)