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

NCT03276078 | Completed Phase 2 Results

• 2 other identifiers: D6572C00001M-AS464-01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

COPD

Outcome Measures

Primary Outcomes (18)

• 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 Outcomes (6)

• Adverse Events (AEs)/Serious AEs (SAEs)

  Screening (Day -21) to Follow-up visit (Days 8-12)

• Treatment-emergent AEs Related to Blood Pressure

  Screening (Day -21) to Follow-up visit (Days 8-12)

• Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)

  Screening (Day -21) to Follow-up visit (Days 8-12)

• Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)

  Screening (Day -21) to Follow-up visit (Days 8-12)

• Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)

  Screening (Day -21) to Follow-up visit (Days 8-12)

Study Arms (1)

Aclidinium Bromide/Formoterol Fumarate 400/12μg BID

EXPERIMENTAL

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

Interventions

Aclidinium Bromide/Formoterol Fumarate 400/12μg BID DRUG

Aclidinium bromide/formoterol fumarate 400/12μg administered by inhalation via the Genuair® multidose dry powder inhaler, twice daily (morning and evening) for 5 days

Aclidinium Bromide/Formoterol Fumarate 400/12μg BID

Eligibility Criteria

• Age: 40 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Changchun, 130021, China

Location

Related Publications (1)

• Zhang H, Daoud SZ, Gillen MS, Calderon N, Heijer M, Molins E, Garcia-Gil E, Chen H, Li Q, Liu C, Ding Y. An Evaluation of the Pharmacokinetics, Safety, and Tolerability of Aclidinium/Formoterol Fixed-Dose Combination Administered in Chinese Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease. Drugs R D. 2022 Mar;22(1):35-42. doi: 10.1007/s40268-021-00374-z. Epub 2022 Feb 8.

  PMID: 35133636 DERIVED

Related Links

• Statistical Analysis Plan (SAP)
• Protocol

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

aclidinium bromide; Formoterol Fumarate; BID protein, human

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines

Limitations and Caveats

A possible limitation of the study is the high between-participant variability, which was likely related to suboptimal inhalation technique in many participants.

Results Point of Contact

• Title: Dr Sami Daoud
• Organization: AstraZeneca PLC

Information.centre@astrazeneca.com

1-877-240-9479

Study Officials

• Zhenxiang Yu

  Pneumology Department, The First Hospital of Jilin University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 7, 2017
• First Posted: September 8, 2017
• Study Start: November 23, 2017
• Primary Completion: June 12, 2018
• Study Completion: June 12, 2018
• Last Updated: July 22, 2019
• Results First Posted: July 22, 2019

Record last verified: 2019-05

Locations

CN (1)