Clinical trial NCT02777827: A Single Dose PD & PK Study With Two Formulations of Abediterol in Patients With Asthma
Official title: A Randomised, Double-Blinded, Double-Dummy, Placebo-Controlled, MultiCentre-, Six-Way, Crossover Study to Assess the Pharmacodynamics, Pharmacokinetics, and Safety of Abediterol Single Dose, Given by Dry Powder Inhaler (DPI) or Pressurised Metered-Dose Inhaler (pMDI), in Patients With Asthma on Inhaled Corticosteroids.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Asthma
Keywords: Abediterol
Dry powder inhaler
Pressured metered-dose inhaler
Pharmacokinetic
Pharmacodynamic
Safety
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2016-05-19
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate the pharmacodynamics of single doses of abediterol given by 2 different devices in participants with asthma. Abediterol (AZD0548) is a potential for once daily treatment of asthma and chronic obstructive pulmonary disease (COPD) in fixed dose combination (FDC) with an inhaled corticosteroid (ICS) or a novel anti-inflammatory agent. The aim of the clinical studies is to enable further investigations in participants with asthma and COPD to evaluate and develop abediterol as an effective long acting bronchodilator with an acceptable safety profile compared to other inhaled bronchodilators on the market, for the treatment of asthma and COPD.

Detailed description: This is a randomised, double-blinded, double-dummy, placebo-controlled, multi-centre, six-way William's design, crossover study to assess the pharmacodynamics, pharmacokinetics, and safety of abediterol single dose, given by dry powder inhaler or pressurised metered-dose inhaler, in patients with asthma, on inhaled corticosteroids. During the screening period, all patients will take their own baseline inhaled corticosteroid for 2 weeks. Patients on long-acting β2-agonist/ inhaled corticosteroids will be switched over to the respective inhaled corticosteroid monocomponent. Patients will be provided salbutamol as rescue medication for use throughout the study. Abediterol is an investigational product in early stages of clinical development, therefore individual participants in the clinical studies may not have a clinical benefit, especially in view of alternative therapies (bronchodilators) being available for the treatment of asthma and COPD.

Eligibility criteria: Inclusion Criteria:

1. Provision of informed consent before any study specific procedures.
2. Men or non-pregnant, non-lactating women 18 to 75 years of age, inclusive.
3. Non-smoker or ex-smoker (quit ≥6months prior to Visit 1) with a total smoking history of ≤10 pack years.
4. Documented clinical diagnosis of asthma for ≥6 months before Visit 1 according to GINA guidelines.
5. On stable dose of ICS or ICS/LABA FDC, for at least 1 month prior to Visit 1, at the doses approved in the country of enrolment.
6. Prebronchodilator FEV1 at Visit 2 ≥40% and ≤85% of predicted (1 repetition of the test is allowed before screen failure).
7. Reversibility to salbutamol (per American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria, 2005 ie, ≥12% and ≥200 mL) at Visit 2 (1 repetition of the test is allowed before screen failure).
8. Demonstrate the ability to use the study inhalation device properly.
9. Able to perform repeated pulmonary function testing for FEV1.
10. Able to read, speak and understand German.
11. Patient must agree to all restrictions during the study.

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
2. Participation in another clinical study with an IP during the last 3 months.
3. Known or suspected hypersensitivity to the IP or excipients, including lactose (Note: lactose intolerance is not an exclusion).
4. Systemic steroid use in the 6 weeks before Visit 1.
5. Hospitalization due to asthma in the 6 months prior to Visit 1.
6. Any active pulmonary disease other than asthma.
7. Non-compliance with study procedures in the run in period - as judged by the Investigator.
8. Treatment with biologicals such as monoclonal antibodies or chimeric biomolecules including omalizumab within 6 months or 5 half-lives before Visit 1 (whichever is longer).
9. Treatment with any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to Visit 1.
10. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to Visit 1.
11. Any laboratory abnormality or suspicion of any clinically relevant disease or disorder (on history or examination), including uncontrolled hypertension or uncontrolled diabetes, 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.
12. Known chronic hepatitis or HIV infections at the time of enrolment.
13. Any active malignancy or treatment thereof within the 3 years prior to enrolment.
14. Any clinically important abnormalities in rhythm, conduction, or morphology of the screening 12-lead ECG as judged by the Investigator on the screening ECG.
15. Prolonged QT interval using Fridericia's correction 450 msec for males and 470 msec for females on the screening ECG or family history of long QT syndrome.
16. PR (PQ) interval prolongation (\> 240 msec), intermittent second or third degree atrialventricular (AV) block or AV dissociation on the screening ECG.
17. Implantable cardiac defibrillator and patients with sustained symptomatic ventricular and/or atrial tachyarrhythmia.
18. Any contraindication against the use of sympathomimetic drugs as judged by the Investigator.
19. Unstable angina pectoris or stable angina pectoris classified higher than Canadian Cardiovascular Society Class II, or a myocardial infarction, or stroke within 6 months before Visit 1.
20. History of hospitalisation within 12 months caused by heart failure or a diagnosis of heart failure higher than New York Heart Association Class II.
21. Suspected poor capability to follow instructions of the study, as judged by the Investigator.
22. History of or current alcohol or drug abuse (including marijuana), as judged by the Investigator.
23. Planned in-patient surgery, major dental procedure or hospitalisation during the study.
24. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff, contract research organisation staff and/or staff at the study site).
25. Vulnerable persons (eg, persons kept in detention). 26 Daily rescue medication (salbutamol) use of ≥ 12 puffs for ≥ 3 consecutive days during the run-in period.

27. Patient who intends to use any concomitant medication not permitted by this protocol or not to meet the restrictions.

28. Patient on treatment with strong CYP3A4 inhibitors such as ketoconazole or itraconazole or CYP3A4 inducers such as rifampin at Visit 1.

29. Procedures for withdrawal of incorrectly enrolled patients.

Primary outcomes:
measure: Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1).
timeFrame: 45 mins and 15 mins pre-dose, and 23.00-24.00 h post-dose on Day 1
Secondary outcomes:
measure: Percentage of Participants Achieving a ≥ 200 mL and ≥12% Increase From Baseline in Peak FEV1 on Day 1.
timeFrame: Predose and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1
measure: Time to Peak FEV1 at Day 1
timeFrame: 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1
measure: Observed Maximum Concentration of Abediterol (Cmax)
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: Time (h) to Maximum Concentration of Abediterol (Tmax).
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: Terminal Rate Constant of Abediterol (λz)
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: Terminal Half-life (h) of Abediterol (t½λz)
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: AUClast of Abediterol
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: AUC of Abediterol.
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: Apparent Plasma Clearance for Abediterol (CL/F).
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: Apparent Volume of Distribution for Abediterol at Terminal Phase (Vz/F).
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: Mean Residence Time (MRT) of Abediterol.
timeFrame: Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1.
measure: Number of Participants With Any Treatment-emergent Adverse Event
timeFrame: From screening (Day -14) up to follow-up phone call (14 days after last IP administration).
measure: Number of Participants With Post-baseline Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters
timeFrame: Up to last treatment visit (Day 112)
measure: Time to Peak FVC at Day 1
timeFrame: 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1
measure: Percentage of Participants Achieving a ≥ 200 mL and ≥12% Increase From Baseline in Trough FEV1.
timeFrame: Predose and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1
measure: Change From Baseline in Peak FEV1.
timeFrame: Predose and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1
measure: Change From Baseline in Normalised FEV1 AUC0-24.
timeFrame: 45 mins and 15 mins predose, and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h, 6 h, 12 h, 16 h, 22 h, and 23.00-24.00 h post-dose on Day 1
measure: Change From Baseline in Normalised FEV1 AUC0-12.
timeFrame: 45 mins and 15 mins predose, and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h, 6 h, and 12 h post-dose on Day 1
measure: Change From Baseline in Normalised FEV1 AUC0-6.
timeFrame: 45 mins and 15 mins predose, and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h, and 6 h post dose on Day 1
measure: Change From Baseline in Normalised FEV1 AUC12-24.
timeFrame: 45 mins and 15 mins predose, and 12 h, 16 h, 22 h, and 23.00-24.00 h post-dose on Day 1
measure: Change From Baseline in Peak FVC.
timeFrame: Predose and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1
measure: Change From Baseline in Trough FVC.
timeFrame: 45 mins and 15 mins pre-dose, and 23.00-24.00 h post-dose on Day 1
measure: Change From Baseline in Normalised FVC AUC0-24.
timeFrame: 45 mins and 15 mins predose, and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h, 6 h, 12 h, 16 h, 22 h, and 23.00-24.00 h post-dose on Day 1
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Research Site
city: Großhansdorf
country: Germany
facility: Research Site
city: Lübeck
country: Germany
facility: Research Site
city: Wiesbaden
country: Germany
facility: Research Site
Study officials:
affiliation: Biebricher Allee 34, Wiesbaden, Germany, 65187.
name: Jutta Beier, Dr
role: PRINCIPAL_INVESTIGATOR
References: