Pharmacokinetics, Safety and Tolerability of Twice-Daily Aclidinium Bromide/Formoterol Fumarate Fixed Dose Combination in Chinese Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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A Phase IIa, open-label, repeat-dose trial to investigate the pharmacokinetics (PK), safety and tolerability of single and multiple twice daily doses of inhaled Aclidinium Bromide/Formoterol Fumarate 400/12 μg in 20 Chinese male and female patients with stable moderate to severe COPD.

Detailed Description
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Screening will be performed within 21 days of dosing on Day 1 at visit 2. Eligible participants will be admitted to the trial center the day preceding the first dosing (day -1). Participants will receive Aclidinium Bromide/Formoterol Fumarate 400/12 μg twice-daily (morning and evening) on Days 1 to 4. On Day 5 patients will receive the morning dose only. PK and safety assessments will be conducted at specific timepoints on Day 1 to Day 7. Participants will be discharged 48 h after the last administration of investigational product and completion of the 48-h PK sample collection and safety assessments on Day 7. A follow-up visit will be performed within 5 days of the last PK sample collection on Day 7.

Official Title
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A Phase IIa, Open-Label, Repeat-Dose Clinical Trial to Evaluate the Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Fixed Dose Combination Administered Twice-Daily by Inhalation in Chinese Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Aclidinium Bromide/Formoterol Fumarate 400/12μg BID


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to communicate with medical team and staff, willing to participate in the trial, willing to give written informed consent, and comply with the trial procedures and restrictions. Chinese men or non-pregnant, non-lactating women, aged ≥40 years old at Visit 1 (Screening). Patients with a diagnosis of COPD (GOLD guidelines) for a period of at least 6 months prior to Visit 1 (screening). Current or former smokers with a smoking history of ≥10 pack-years. Patients with moderate to severe stable COPD (Stage II or Stage III, according to GOLD Guidelines) at Visit 1: post-bronchodilator FEV1 ≥30% and <80% and post-bronchodilator FEV1/FVC <70%. Must be able to perform repeatable pulmonary function testing for FEV1 according to ATS/ERS 2005 criteria at Visit 1 (Screening). Exclusion Criteria: Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff) or patients employed by or relatives of the employees of the site or sponsor. Previous enrolment or randomisation in the present study. History or current diagnosis of asthma. Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening or during the run-in period. Patients hospitalized for COPD exacerbation (an emergency room visit for longer than 24 hours will be considered a hospitalization) within 3 months prior to screening and during the run-in period. Use of long-term oxygen therapy ≥15 hours per day. Patient with a history of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, inhaled medication, or any component thereof. Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic nonstable prostatic hypertrophy. Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypothyroidism or hyperthyroidism, hypokalaemia, hyperadrenergic state, or uncontrolled or untreated hypertension. Clinically significant cardiovascular conditions. Patient with resting systolic blood pressure ≥160 mmHg, a resting diastolic blood pressure ≥100 mmHg, or a resting heart rate ≤50 bpm or ≥100 bpm at Visit 1 (Screening) or/and at Visit 2 (Day -1 to Day 7). Have a body mass index (BMI) ≥40 kg/m2 Electrocardiogram (ECG) at Screening or Day -1 showing corrected QT interval (QTc) using Fridericia's correction (QTcF) >470 msec. Patients with clinically relevant abnormalities in the results of the laboratory tests, ECG parameters (other than QTcF), or in the physical examination at Visit 1, except those related to COPD. Positive results for drugs of abuse in the urine at Visit 1 (Screening). Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody and/or human immunodeficiency virus (HIV) I antibodies at Visit 1 (Screening). History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer. Any other serious or uncontrolled physical or mental condition/disease. Patient with a history (within 2 years prior to Visit 1 [Screening]) of drug and/or alcohol abuse that may prevent trial compliance based on investigator judgment. Taken any medication within 14 days before the first dose of IP, or hormonal drug products and traditional Chinese medicines within 30 days before the first dose of IP, with the exception of allowed medications listed in the study protocol. Participation in any other clinical investigation using an experimental drug requiring repeated blood or plasma drawn within 60 days of Day 1 at Visit 2. Have participated in a blood/plasma donation or blood loss greater than 400 mL within 90 days or greater than 200 mL within 30 days prior to Visit 1 (Screening). Have any clinical condition that might affect the absorption, distribution, biotransformation, or excretion of Aclidinium Bromide/Formoterol Fumarate. Have consumed caffeine or any grapefruit-containing products within 48 hours or alcohol within 72 hours before Day -1 at Visit 2. Inability to be venipunctured or tolerate venous access as determined by the investigator or designee. Inability to use a multidose DPI. Subjects unable to give their consent, or subjects of consenting age but under guardianship, or vulnerable subjects. In the opinion of the PI, subjects who are unlikely to comply with the protocol requirements, instructions, and trial-related restrictions. Previously taken Aclidinium or previously participated in an investigational study of Aclidinium within 6 months of Day 1

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aclidinium Bromide/Formoterol Fumarate 400/12μg BID<br>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI). | Drug: Aclidinium Bromide/Formoterol Fumarate 400/12μg BID<br>* Aclidinium bromide/formoterol fumarate 400/12μg administered by inhalation via the Genuair® multidose dry powder inhaler, twice daily (morning and evening) for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). | Observed maximum concentration, taken directly from the individual concentration-time curve (first dose). | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1 | 
| Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). | Time to maximum concentration (h), taken directly from the individual concentration-time curve (first dose). | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1 | 
| Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). | Minimum plasma drug concentration at the end of the dosing interval (first dose), where possible. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1 | 
| AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). | Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1 | 
| AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). | Area under the plasma concentration curve during the first dosing interval, tau (first dose). | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1 | 
| Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Observed maximum concentration, taken directly from the individual concentration-time curve at steady state. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 5. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Time to maximum concentration (h), taken directly from the individual concentration-time curve at steady state. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Terminal rate constant, estimated by log-linear least square regression of the terminal part of the concentration-time curve. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Terminal half-life (h), estimated as (ln2)/λz. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Area under the plasma concentration curve during the dosing interval, tau at steady state. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses). | Apparent plasma clearance for parent drug estimated as dose divided by AUCss | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses). | Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12 | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| %Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Fluctuation index during a dosing interval estimated as 100*(Cmax-Cmin)/Cav (%). | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Accumulation ratio for Cmax estimated as Css,max on Day 5/Cmax on Day 1 | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Accumulation ratio for AUC(tau) estimated as AUC(ss,tau) on Day 5/AUC(tau) on Day 1 | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 
| Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). | Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1. Additional parameters may be determined where appropriate. | Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs)/Serious AEs (SAEs) | Assessment of the safety in terms of the incidences of AEs/SAEs after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days. | Screening (Day -21) to Follow-up visit (Days 8-12) | 
| Treatment-emergent AEs Related to Blood Pressure | Assessment of the safety in terms of notable changes from baseline in blood pressure after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days. | Screening (Day -21) to Follow-up visit (Days 8-12) | 
| Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology) | Assessment of the safety in terms of haematology parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days. | Screening (Day -21) to Follow-up visit (Days 8-12) | 
| Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis) | Assessment of the safety in terms of urinalysis parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days. | Screening (Day -21) to Follow-up visit (Days 8-12) | 
| Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry) | Assessment of the safety in terms of serum biochemistry parameters (Alanine aminotransferase [ALT], Aspartate aminotransferase [AST], alkaline phosphatase [ALP], Gamma-glutamyl transferase [GGT], bilirubin, creatine kinase, lactate dehydrogenase, urea nitrogen, creatinine, urate, cholesterol, glucose, sodium, potassium, calcium, chloride, phosphate, protein, and albumin) after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days. | Screening (Day -21) to Follow-up visit (Days 8-12) | 
| Treatment-emergent AEs Related to 12-lead ECG Parameters | Assessment of the safety in terms of the 12-lead ECG parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days. | Screening (Day -21) to Follow-up visit (Days 8-12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD