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

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.

Inclusion criteria

Part 1

• Subjects who are able and willing to provide written informed consent prior to conducting any study-related procedures, including withdrawal of medications
• Adult male subjects aged 18 to 70 years (both inclusive)
• Body mass index (BMI) from 18 to 32 kg/m2 at screening
• Clinical diagnosis of asthma (according to the Global Initiative for Asthma [GINA] guidelines) for at least 6 months prior to screening
• Ability to change current asthma therapy, to discontinue previous prescribed medications after signature of informed consent as per required washout periods
• Screening FEV1 value of ≥70% of the predicted normal value
• 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
• 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
• Predose FEV1 value of first treatment period within the range of ± 20% of the FEV1 measured at screening prior to salbutamol inhalation
• 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
• No other relevant pulmonary disease or history of thoracic surgery
• Subjects who are otherwise healthy as determined by medical history, physical examination, 12-lead ECG findings
• 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
• Subjects whose clinical laboratory test results are not clinically relevant and are acceptable to the Investigator.
• 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
• Subjects who are negative for drugs of abuse and alcohol tests at screening and admission
• 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

• 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
• Females must be of non-childbearing potential, confirmed at screening by fulfilling study predefined criteria
• Post-salbutamol FEV1 <80% and ≥30% of the predicted normal value and post-salbutamol FEV1 / forced vital capacity (FVC) <70%
• BMI < 40 kg/m2 at screening
• Ability to change current COPD therapy, to discontinue previous prescribed medications after signature of informed consent as per required washout periods
• Current or ex-smokers with a smoking history of ≥10 pack years
• No evidence of clinically significant respiratory and / or cardiovascular conditions (e.g. uncontrolled hypertension) or laboratory abnormalities
• No other relevant pulmonary disease or history of thoracic surgery
• Subjects who are negative for HBsAg, HBc IgM, hepatitis C antibody and HIV I and II antibodies at screening
• Subjects who are able and willing to provide written informed consent prior to conducting any study-related procedures, including withdrawal of medications
• Medical history must be verified by either a personal physician or medical practitioner as appropriate
• 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):

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
• Previous enrolment or randomisation of treatment in the present study
• 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
• Subjects with a surgical history clinically relevant for the purpose of the study
• 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
• 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)
• Current diagnosis of COPD (for Part 1 only) or history of / or current diagnosis for asthma (for Part 2 only)
• 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
• Use of daily oxygen therapy >10 h per day (for Part 2 only)
• Use of systemic steroids for respiratory reasons within 6 weeks prior to screening
• Lower respiratory tract infection within 6 weeks prior to screening or prior to randomisation
• Upper respiratory tract infection requiring antibiotics within 6 weeks prior to screening or prior to randomisation
• Current history of tuberculosis, bronchiectasis or other non-specific pulmonary disease
• Subject with significant cardiovascular disease that may be vulnerable to cardiovascular instability
• 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
• 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
• Subjects with serum potassium concentration < 3.5mmol/l at screening
• Subjects with a history of excessive use or abuse of alcohol within the past 2 years
• Subjects with a history of drug abuse within the past 2 years
• 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
• Donation or loss >400 ml of blood and plasma within the previous 3 months prior to screening
• Subjects with a significant infection or known inflammatory process at screening or prior to randomisation
• Subjects with acute gastrointestinal symptoms at the time of screening or prior to randomisation (eg, nausea, vomiting, diarrhoea, heartburn)
• Subjects with an acute infection such as influenza at the time of screening or prior to randomisation
• Male subjects who do not agree to follow instructions to avoid pregnancies
• Subjects who are not able to adhere to the restrictions on prior and concomitant medications
• 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
• 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
• Subjects who have received the last dose of investigational product more than 3 months ago but who are on an extended follow-up
• 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