Two-part Safety, Tolerability, Pharmacodynamic and -Kinetic Study of Inhaled AZD8871 in Asthmatic and COPD Subjects
Condition: Asthma (Part 1); COPD (Part 2)
MeSH terms: Asthma
Intervention: Dose 1, AZD8871 50 μg (Part 1); Dose 2, AZD8871 100 μg (Part 1); Dose 3, AZD8871 300 μg (Part 1); Dose 4, AZD8871 600 µg (Part 1); Dose 5, AZD8871 1200 µg (Part 1); Dose 6, AZD8871 1800 μg (Part 1); Placebo, AZD8871 placebo (Part 1); Treatment A, AZD8871 dose A (Part 2); Treatment B, AZD8871 dose B (Part 2); Treatment C, Indacaterol 150 μg (Part 2); Treatment D, Tiotropium 18 μg (Part 2)
Intervention description: 50 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); 100 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); 300 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); 600 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); 1200 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); 1800 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®); AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®); 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; 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
Intervention MeSH terms: Tiotropium Bromide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Enrollment: 134.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Pharmacokinetics; Pharmacodynamics; AZD8871; Safety; Tolerability; mild persistent asthma; moderate to severe COPD

Summary:

      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.
    

Eligibility criteria:

        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