<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03276078</url>
  </required_header>
  <id_info>
    <org_study_id>D6572C00001</org_study_id>
    <secondary_id>M-AS464-01</secondary_id>
    <nct_id>NCT03276078</nct_id>
  </id_info>
  <brief_title>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</brief_title>
  <official_title>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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AstraZeneca</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A Phase IIa, open-label, repeat-dose trial to investigate the pharmacokinetics (PK), safety&#xD;
      and tolerability of single and multiple twice daily doses of inhaled Aclidinium&#xD;
      Bromide/Formoterol Fumarate 400/12 μg in 20 Chinese male and female patients with stable&#xD;
      moderate to severe COPD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Screening will be performed within 21 days of dosing on Day 1 at visit 2. Eligible&#xD;
      participants will be admitted to the trial center the day preceding the first dosing (day&#xD;
      -1).&#xD;
&#xD;
      Participants will receive Aclidinium Bromide/Formoterol Fumarate 400/12 μg twice-daily&#xD;
      (morning and evening) on Days 1 to 4. On Day 5 patients will receive the morning dose only.&#xD;
      PK and safety assessments will be conducted at specific timepoints on Day 1 to Day 7.&#xD;
&#xD;
      Participants will be discharged 48 h after the last administration of investigational product&#xD;
      and completion of the 48-h PK sample collection and safety assessments on Day 7.&#xD;
&#xD;
      A follow-up visit will be performed within 5 days of the last PK sample collection on Day 7.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 23, 2017</start_date>
  <completion_date type="Actual">June 12, 2018</completion_date>
  <primary_completion_date type="Actual">June 12, 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</measure>
    <time_frame>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</time_frame>
    <description>Observed maximum concentration, taken directly from the individual concentration-time curve (first dose).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</measure>
    <time_frame>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</time_frame>
    <description>Time to maximum concentration (h), taken directly from the individual concentration-time curve (first dose).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</measure>
    <time_frame>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</time_frame>
    <description>Minimum plasma drug concentration at the end of the dosing interval (first dose), where possible.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</measure>
    <time_frame>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</time_frame>
    <description>Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</measure>
    <time_frame>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</time_frame>
    <description>Area under the plasma concentration curve during the first dosing interval, tau (first dose).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Observed maximum concentration, taken directly from the individual concentration-time curve at steady state.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 5.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Time to maximum concentration (h), taken directly from the individual concentration-time curve at steady state.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Terminal rate constant, estimated by log-linear least square regression of the terminal part of the concentration-time curve.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Terminal half-life (h), estimated as (ln2)/λz.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Area under the plasma concentration curve during the dosing interval, tau at steady state.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Apparent plasma clearance for parent drug estimated as dose divided by AUCss</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12</description>
  </primary_outcome>
  <primary_outcome>
    <measure>%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Fluctuation index during a dosing interval estimated as 100*(Cmax-Cmin)/Cav (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Accumulation ratio for Cmax estimated as Css,max on Day 5/Cmax on Day 1</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Accumulation ratio for AUC(tau) estimated as AUC(ss,tau) on Day 5/AUC(tau) on Day 1</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</measure>
    <time_frame>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</time_frame>
    <description>Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1.&#xD;
Additional parameters may be determined where appropriate.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse Events (AEs)/Serious AEs (SAEs)</measure>
    <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment-emergent AEs Related to Blood Pressure</measure>
    <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)</measure>
    <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
    <description>Assessment of the safety in terms of haematology parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)</measure>
    <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
    <description>Assessment of the safety in terms of urinalysis parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)</measure>
    <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment-emergent AEs Related to 12-lead ECG Parameters</measure>
    <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <arm_group>
    <arm_group_label>Aclidinium Bromide/Formoterol Fumarate 400/12μg BID</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aclidinium Bromide/Formoterol Fumarate 400/12μg BID</intervention_name>
    <description>Aclidinium bromide/formoterol fumarate 400/12μg administered by inhalation via the Genuair® multidose dry powder inhaler, twice daily (morning and evening) for 5 days</description>
    <arm_group_label>Aclidinium Bromide/Formoterol Fumarate 400/12μg BID</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability to communicate with medical team and staff, willing to participate in the&#xD;
             trial, willing to give written informed consent, and comply with the trial procedures&#xD;
             and restrictions.&#xD;
&#xD;
          -  Chinese men or non-pregnant, non-lactating women, aged ≥40 years old at Visit 1&#xD;
             (Screening).&#xD;
&#xD;
          -  Patients with a diagnosis of COPD (GOLD guidelines) for a period of at least 6 months&#xD;
             prior to Visit 1 (screening).&#xD;
&#xD;
          -  Current or former smokers with a smoking history of ≥10 pack-years.&#xD;
&#xD;
          -  Patients with moderate to severe stable COPD (Stage II or Stage III, according to GOLD&#xD;
             Guidelines) at Visit 1: post-bronchodilator FEV1 ≥30% and &lt;80% and post-bronchodilator&#xD;
             FEV1/FVC &lt;70%.&#xD;
&#xD;
          -  Must be able to perform repeatable pulmonary function testing for FEV1 according to&#xD;
             ATS/ERS 2005 criteria at Visit 1 (Screening).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff&#xD;
             and/or site staff) or patients employed by or relatives of the employees of the site&#xD;
             or sponsor.&#xD;
&#xD;
          -  Previous enrolment or randomisation in the present study.&#xD;
&#xD;
          -  History or current diagnosis of asthma.&#xD;
&#xD;
          -  Any respiratory tract infection (including the upper respiratory tract) or COPD&#xD;
             exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening&#xD;
             or during the run-in period.&#xD;
&#xD;
          -  Patients hospitalized for COPD exacerbation (an emergency room visit for longer than&#xD;
             24 hours will be considered a hospitalization) within 3 months prior to screening and&#xD;
             during the run-in period.&#xD;
&#xD;
          -  Use of long-term oxygen therapy ≥15 hours per day.&#xD;
&#xD;
          -  Patient with a history of hypersensitivity reaction to inhaled anticholinergics,&#xD;
             sympathomimetic amines, inhaled medication, or any component thereof.&#xD;
&#xD;
          -  Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute&#xD;
             urinary retention, or patients with symptomatic nonstable prostatic hypertrophy.&#xD;
&#xD;
          -  Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypothyroidism or&#xD;
             hyperthyroidism, hypokalaemia, hyperadrenergic state, or uncontrolled or untreated&#xD;
             hypertension.&#xD;
&#xD;
          -  Clinically significant cardiovascular conditions.&#xD;
&#xD;
          -  Patient with resting systolic blood pressure ≥160 mmHg, a resting diastolic blood&#xD;
             pressure ≥100 mmHg, or a resting heart rate ≤50 bpm or ≥100 bpm at Visit 1 (Screening)&#xD;
             or/and at Visit 2 (Day -1 to Day 7).&#xD;
&#xD;
          -  Have a body mass index (BMI) ≥40 kg/m2&#xD;
&#xD;
          -  Electrocardiogram (ECG) at Screening or Day -1 showing corrected QT interval (QTc)&#xD;
             using Fridericia's correction (QTcF) &gt;470 msec.&#xD;
&#xD;
          -  Patients with clinically relevant abnormalities in the results of the laboratory&#xD;
             tests, ECG parameters (other than QTcF), or in the physical examination at Visit 1,&#xD;
             except those related to COPD.&#xD;
&#xD;
          -  Positive results for drugs of abuse in the urine at Visit 1 (Screening).&#xD;
&#xD;
          -  Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody and/or&#xD;
             human immunodeficiency virus (HIV) I antibodies at Visit 1 (Screening).&#xD;
&#xD;
          -  History of malignancy of any organ system (including lung cancer), treated or&#xD;
             untreated, within the past 5 years other than basal or squamous cell skin cancer.&#xD;
&#xD;
          -  Any other serious or uncontrolled physical or mental condition/disease.&#xD;
&#xD;
          -  Patient with a history (within 2 years prior to Visit 1 [Screening]) of drug and/or&#xD;
             alcohol abuse that may prevent trial compliance based on investigator judgment.&#xD;
&#xD;
          -  Taken any medication within 14 days before the first dose of IP, or hormonal drug&#xD;
             products and traditional Chinese medicines within 30 days before the first dose of IP,&#xD;
             with the exception of allowed medications listed in the study protocol.&#xD;
&#xD;
          -  Participation in any other clinical investigation using an experimental drug requiring&#xD;
             repeated blood or plasma drawn within 60 days of Day 1 at Visit 2.&#xD;
&#xD;
          -  Have participated in a blood/plasma donation or blood loss greater than 400 mL within&#xD;
             90 days or greater than 200 mL within 30 days prior to Visit 1 (Screening).&#xD;
&#xD;
          -  Have any clinical condition that might affect the absorption, distribution,&#xD;
             biotransformation, or excretion of Aclidinium Bromide/Formoterol Fumarate.&#xD;
&#xD;
          -  Have consumed caffeine or any grapefruit-containing products within 48 hours or&#xD;
             alcohol within 72 hours before Day -1 at Visit 2.&#xD;
&#xD;
          -  Inability to be venipunctured or tolerate venous access as determined by the&#xD;
             investigator or designee.&#xD;
&#xD;
          -  Inability to use a multidose DPI.&#xD;
&#xD;
          -  Subjects unable to give their consent, or subjects of consenting age but under&#xD;
             guardianship, or vulnerable subjects.&#xD;
&#xD;
          -  In the opinion of the PI, subjects who are unlikely to comply with the protocol&#xD;
             requirements, instructions, and trial-related restrictions.&#xD;
&#xD;
          -  Previously taken Aclidinium or previously participated in an investigational study of&#xD;
             Aclidinium within 6 months of Day 1&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>130 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zhenxiang Yu</last_name>
    <role>Principal Investigator</role>
    <affiliation>Pneumology Department, The First Hospital of Jilin University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Changchun</city>
        <zip>130021</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <link>
    <url>http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&amp;studyid=4100&amp;filename=d6572c00001-sap-ed-2_Redacted.pdf</url>
    <description>Statistical Analysis Plan (SAP)</description>
  </link>
  <link>
    <url>http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&amp;studyid=4100&amp;filename=d6572c00001-pk-csp-v1_Redacted.pdf</url>
    <description>Protocol</description>
  </link>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>September 7, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <results_first_submitted>May 14, 2019</results_first_submitted>
  <results_first_submitted_qc>May 14, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">July 22, 2019</results_first_posted>
  <last_update_submitted>May 14, 2019</last_update_submitted>
  <last_update_submitted_qc>May 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COPD</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bromides</mesh_term>
    <mesh_term>Formoterol Fumarate</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 3, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/78/NCT03276078/SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 24, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/78/NCT03276078/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study was conducted at a single centre in China. The first participant was enrolled in December 2017 and the last participant visit was in June 2018.</recruitment_details>
      <pre_assignment_details>A total of 97 participants were screened. Of these, 20 were enrolled and received treatment.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>AB/FF 400/12 BID</title>
          <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Safety analysis set: Includes all participants who received at least one dose of investigational product.</population>
      <group_list>
        <group group_id="B1">
          <title>AB/FF 400/12 BID</title>
          <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.2" spread="6.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
        <description>Observed maximum concentration, taken directly from the individual concentration-time curve (first dose).</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
          <description>Observed maximum concentration, taken directly from the individual concentration-time curve (first dose).</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>pg/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.82" spread="84.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3149" spread="55.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.82" spread="86.60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.786" spread="62.78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
        <description>Time to maximum concentration (h), taken directly from the individual concentration-time curve (first dose).</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
          <description>Time to maximum concentration (h), taken directly from the individual concentration-time curve (first dose).</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.08" lower_limit="0.08" upper_limit="0.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.00" lower_limit="1.50" upper_limit="6.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.75" lower_limit="0.08" upper_limit="4.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.00" lower_limit="0.08" upper_limit="3.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
        <description>Minimum plasma drug concentration at the end of the dosing interval (first dose), where possible.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
          <description>Minimum plasma drug concentration at the end of the dosing interval (first dose), where possible.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>pg/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide Not calculable</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="627.7" spread="52.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823 Not calculable</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate Not calculable</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
        <description>Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
          <description>Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>pg*hour/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="78.61" spread="90.69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20280" spread="54.28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="201.1" spread="106.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.04" spread="64.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
        <description>Area under the plasma concentration curve during the first dosing interval, tau (first dose).</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).</title>
          <description>Area under the plasma concentration curve during the first dosing interval, tau (first dose).</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>pg*hour/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85.45" spread="79.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20330" spread="54.24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="252.9" spread="60.63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.78" spread="43.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Observed maximum concentration, taken directly from the individual concentration-time curve at steady state.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Observed maximum concentration, taken directly from the individual concentration-time curve at steady state.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>pg/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.86" spread="150.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3691" spread="56.03"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81.02" spread="69.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.465" spread="84.34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 5.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 5.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>pg/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.528" spread="47.34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1032" spread="43.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.88" spread="47.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.281" spread="36.63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Time to maximum concentration (h), taken directly from the individual concentration-time curve at steady state.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Time to maximum concentration (h), taken directly from the individual concentration-time curve at steady state.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.08" lower_limit="0.08" upper_limit="0.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.00" lower_limit="0.08" upper_limit="4.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.08" upper_limit="3.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.08" lower_limit="0.08" upper_limit="1.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Terminal rate constant, estimated by log-linear least square regression of the terminal part of the concentration-time curve.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Terminal rate constant, estimated by log-linear least square regression of the terminal part of the concentration-time curve.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>1/hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.053" spread="0.040"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.045" spread="0.018"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.048" spread="0.021"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.057" spread="0.029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Terminal half-life (h), estimated as (ln2)/λz.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Terminal half-life (h), estimated as (ln2)/λz.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.42" spread="11.10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.95" spread="18.78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.34" spread="8.096"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.06" spread="4.796"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Area under the plasma concentration curve during the dosing interval, tau at steady state.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Area under the plasma concentration curve during the dosing interval, tau at steady state.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>pg*hour/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="168.8" spread="82.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27300" spread="52.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="540.9" spread="54.97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.98" spread="51.60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).</title>
        <description>Apparent plasma clearance for parent drug estimated as dose divided by AUCss</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).</title>
          <description>Apparent plasma clearance for parent drug estimated as dose divided by AUCss</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>L/hour</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3140" spread="2868"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="422.2" spread="222.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).</title>
        <description>Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).</title>
          <description>Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81990" spread="87200"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8284" spread="5161"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>pg/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.07" spread="82.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2275" spread="52.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.07" spread="54.97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.665" spread="51.60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Fluctuation index during a dosing interval estimated as 100*(Cmax-Cmin)/Cav (%).</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Fluctuation index during a dosing interval estimated as 100*(Cmax-Cmin)/Cav (%).</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>Percentage</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="452.5" spread="269.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="117.0" spread="24.69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="132.0" spread="57.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="205.9" spread="90.94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Accumulation ratio for Cmax estimated as Css,max on Day 5/Cmax on Day 1</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Accumulation ratio for Cmax estimated as Css,max on Day 5/Cmax on Day 1</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.297" spread="216.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.185" spread="80.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.070" spread="113.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.384" spread="90.21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Accumulation ratio for AUC(tau) estimated as AUC(ss,tau) on Day 5/AUC(tau) on Day 1</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Accumulation ratio for AUC(tau) estimated as AUC(ss,tau) on Day 5/AUC(tau) on Day 1</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.966" spread="108.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.355" spread="76.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.157" spread="82.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.436" spread="56.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
        <description>Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1.&#xD;
Additional parameters may be determined where appropriate.</description>
        <time_frame>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</time_frame>
        <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).</title>
          <description>Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1.&#xD;
Additional parameters may be determined where appropriate.</description>
          <population>Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.</population>
          <units>ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Aclidinium Bromide</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.877" spread="45.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34850</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.641" spread="69.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LAS34823</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.601" spread="54.86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Formoterol Fumarate</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.822" spread="31.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adverse Events (AEs)/Serious AEs (SAEs)</title>
        <description>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.</description>
        <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
        <population>Safety analysis set: All participants who received at least one dose of the investigational product.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Events (AEs)/Serious AEs (SAEs)</title>
          <description>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.</description>
          <population>Safety analysis set: All participants who received at least one dose of the investigational product.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any AE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any SAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment-emergent AEs Related to Blood Pressure</title>
        <description>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.</description>
        <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
        <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment-emergent AEs Related to Blood Pressure</title>
          <description>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.</description>
          <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Blood pressure increased</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)</title>
        <description>Assessment of the safety in terms of haematology parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.</description>
        <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
        <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)</title>
          <description>Assessment of the safety in terms of haematology parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.</description>
          <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)</title>
        <description>Assessment of the safety in terms of urinalysis parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.</description>
        <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
        <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)</title>
          <description>Assessment of the safety in terms of urinalysis parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.</description>
          <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Urine protein present</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Haematuria</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)</title>
        <description>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.</description>
        <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
        <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)</title>
          <description>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.</description>
          <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment-emergent AEs Related to 12-lead ECG Parameters</title>
        <description>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.</description>
        <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
        <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
        <group_list>
          <group group_id="O1">
            <title>AB/FF 400/12 BID</title>
            <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment-emergent AEs Related to 12-lead ECG Parameters</title>
          <description>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.</description>
          <population>Safety analysis set: All participants who received at least one dose of investigational product.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Screening (Day -21) to Follow-up visit (Days 8-12)</time_frame>
      <desc>The Safety population included all participants who received at least one dose of investigational product.&#xD;
AE summary includes treatment-emergent AEs, that is AEs starting after the first administration of investigational product, until 15 days from last dose.</desc>
      <group_list>
        <group group_id="E1">
          <title>AB/FF 400/12 BID</title>
          <description>Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA version 20.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA version 20.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Protein urine present</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Publication and / or presentation whether complete or partial, of any part of the data or results of this study will not be allowed until global publication and study results disclosure by the sponsor as per EMA / FDA regulatory compliance obligations, and only after mutual agreement between the Investigator and AstraZeneca</restrictive_agreement>
    </certain_agreements>
    <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.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr Sami Daoud</name_or_title>
      <organization>AstraZeneca PLC</organization>
      <phone>1-877-240-9479</phone>
      <email>Information.centre@astrazeneca.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03276078
org study id: D6572C00001
secondary id: M-AS464-01
nct id: NCT03276078
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).
time frame: 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
description: Observed maximum concentration, taken directly from the individual concentration-time curve (first dose).
measure: Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).
time frame: 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
description: Time to maximum concentration (h), taken directly from the individual concentration-time curve (first dose).
measure: Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).
time frame: 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
description: Minimum plasma drug concentration at the end of the dosing interval (first dose), where possible.
measure: AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).
time frame: 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
description: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration.
measure: AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).
time frame: 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
description: Area under the plasma concentration curve during the first dosing interval, tau (first dose).
measure: Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Observed maximum concentration, taken directly from the individual concentration-time curve at steady state.
measure: Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 5.
measure: Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Time to maximum concentration (h), taken directly from the individual concentration-time curve at steady state.
measure: λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Terminal rate constant, estimated by log-linear least square regression of the terminal part of the concentration-time curve.
measure: t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Terminal half-life (h), estimated as (ln2)/λz.
measure: AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Area under the plasma concentration curve during the dosing interval, tau at steady state.
measure: CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Apparent plasma clearance for parent drug estimated as dose divided by AUCss
measure: Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz.
measure: Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12
measure: %Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Fluctuation index during a dosing interval estimated as 100*(Cmax-Cmin)/Cav (%).
measure: Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Accumulation ratio for Cmax estimated as Css,max on Day 5/Cmax on Day 1
measure: Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Accumulation ratio for AUC(tau) estimated as AUC(ss,tau) on Day 5/AUC(tau) on Day 1
measure: Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).
time frame: 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
description: Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1.
Additional parameters may be determined where appropriate.
measure: Adverse Events (AEs)/Serious AEs (SAEs)
time frame: Screening (Day -21) to Follow-up visit (Days 8-12)
description: 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.
measure: Treatment-emergent AEs Related to Blood Pressure
time frame: Screening (Day -21) to Follow-up visit (Days 8-12)
description: 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.
measure: Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)
time frame: Screening (Day -21) to Follow-up visit (Days 8-12)
description: Assessment of the safety in terms of haematology parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.
measure: Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)
time frame: Screening (Day -21) to Follow-up visit (Days 8-12)
description: Assessment of the safety in terms of urinalysis parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.
measure: Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)
time frame: Screening (Day -21) to Follow-up visit (Days 8-12)
description: 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.
measure: Treatment-emergent AEs Related to 12-lead ECG Parameters
time frame: Screening (Day -21) to Follow-up visit (Days 8-12)
description: 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.
arm group label: Aclidinium Bromide/Formoterol Fumarate 400/12μg BID
arm group type: Experimental
description: Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
intervention type: Drug
intervention name: Aclidinium Bromide/Formoterol Fumarate 400/12μg BID
description: Aclidinium bromide/formoterol fumarate 400/12μg administered by inhalation via the Genuair® multidose dry powder inhaler, twice daily (morning and evening) for 5 days
arm group label: Aclidinium Bromide/Formoterol Fumarate 400/12μg BID
criteria: 
gender: All
minimum age: 40 Years
maximum age: 130 Years
healthy volunteers: No
last name: Zhenxiang Yu
role: Principal Investigator
affiliation: Pneumology Department, The First Hospital of Jilin University
facility: 
country: China
url: http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&studyid=4100&filename=d6572c00001-sap-ed-2_Redacted.pdf
description: Statistical Analysis Plan (SAP)
url: http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&studyid=4100&filename=d6572c00001-pk-csp-v1_Redacted.pdf
description: Protocol
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Bromides
mesh term: Formoterol Fumarate
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
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.
point of contact: 