<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/NCT02210806</url>
  </required_header>
  <id_info>
    <org_study_id>API-A006-CL-B3</org_study_id>
    <nct_id>NCT02210806</nct_id>
  </id_info>
  <brief_title>Albuterol DPI (A006) Clinical Study-B3:Efficacy, Dose-ranging and Safety Evaluation</brief_title>
  <acronym>A006-B3</acronym>
  <official_title>Efficacy, Dose-ranging and Safety Evaluation (A Randomized, Double- or Evaluator-blinded, Active- and Placebo-controlled, Single Dose, Five-arm, Crossover, and Dose-ranging Study of A006 in Adult Asthma Patients)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amphastar Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Amphastar Pharmaceuticals, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates the efficacy, dose-ranging and safety profiles of A006, an Albuterol dry&#xD;
      powder inhaler (DPI), in the dose range of 110 to 220 mcg per dose in comparison to a DPI&#xD;
      Placebo Control and an Albuterol metered dose inhaler (MDI) Active Control.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is designed to evaluate the efficacy and safety profiles of A006 and to assist in&#xD;
      identifying the optimum dose of A006 for future clinical studies. Proventil® HFA MDI, a&#xD;
      currently marketed Albuterol MDI product, will be used as an Active Control. The study also&#xD;
      employs a Placebo Control DPI, which has the same configuration as the A006 DPI except that&#xD;
      it contains no active ingredient.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Actual">October 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 Percentage Change (∆%FEV1) from the Same-Day Pre-Dose Baseline</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule. Statistical analysis is performed using a one-sided t-test.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area Under the Curve (AUC[0-6h]) of Placebo Adjusted Post-Dose FEV1 Percentage Change (∆∆%FEV1) from the Same-Day Pre-Dose Baseline</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. ∆∆FEV1% for the study visit is calculated by subtracting the mean ∆%FEV1 for subjects in a randomized treatment arm from their ∆%FEV1. Area under the curve (AUC), from baseline to 6 hours post-dose, for the study visit is calculated using the trapezoidal rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 Volume Changes (∆FEV1) from the Same-Day Pre-Dose Baseline</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Onset of Bronchodilator Effect (t[onset])</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. t[onset] is the point where post-dose ∆%FEV1 first reaches ≥ 12% over the pre-dose baseline. Determined by linear interpolation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Bronchodilator Response (F[max])</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. F[max] is the maximum post-dose ∆%FEV1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Peak ∆FEV1 Effect (t[max])</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. The time to peak ∆FEV1 effect, t[max], is defined as the time of F[max].</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 in Volume from the Same-Day Pre-Dose Baseline</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>F[max] of Post-Dose FEV1 in Volume</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. F[max] of post-dose FEV1 in volume is the maximum post-dose FEV1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy Duration-1</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-1 is total duration of bronchodilator effects when ∆%FEV1 is ≥ 12% above the baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy Duration-2</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-2 is total duration of bronchodilator effects when ∆FEV1 is ≥ 200 mL above the baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy Duration-3</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-3 is total duration of bronchodilator effects when ∆FEV1 is ≥ 100 mL above the baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bronchodilator Response</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Subjects that demonstrate a ≥ 12% increase for ∆%FEV1 will be classified as having a bronchodilator response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dose Response Curve</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. The dose response curve is the AUC[0-6h] of ∆%FEV1 versus study drug dosage.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Systolic and Diastolic Blood Pressure (SBP/DBP) at Screening</measure>
    <time_frame>Within 30 minutes prior to reversibility dosing (baseline) and 30 minutes post-reversibility dosing</time_frame>
    <description>Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to reversibility dosing and 30 minutes after dosing during the Screening Visit.</description>
  </other_outcome>
  <other_outcome>
    <measure>Systolic and Diastolic Blood Pressure (SBP/DBP)</measure>
    <time_frame>Within 1 hour prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at 15 and 30 minutes and 1, 1.5, 2, and 6 hours post-dose during each treatment period.</description>
  </other_outcome>
  <other_outcome>
    <measure>Heart Rate (HR) at Screening</measure>
    <time_frame>Within 30 minutes prior to reversibility dosing (baseline) and 30 minutes post-reversibility dosing</time_frame>
    <description>Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to reversibility dosing and 30 minutes after dosing during the Screening Visit.</description>
  </other_outcome>
  <other_outcome>
    <measure>Heart Rate (HR)</measure>
    <time_frame>Within 1 hour prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at 15 and 30 minutes and 1, 1.5, 2, and 6 hours post-dose during each treatment period.</description>
  </other_outcome>
  <other_outcome>
    <measure>12-Lead ECG QT/QTc Intervals at Screening</measure>
    <time_frame>Within 1 hour prior to reversibility dosing</time_frame>
    <description>12-Lead ECGs are performed to measure QT and QTc intervals prior to reversibility dosing during the Screening Visit.</description>
  </other_outcome>
  <other_outcome>
    <measure>12-Lead ECG QT/QTc Intervals</measure>
    <time_frame>Within 1 hour prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>12-Lead ECGs are performed to measure QT and QTc intervals prior to dosing and at 30 minutes and 1, 2, and 6 hours post-dose during each treatment period.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects with Incidents of Asthma Exacerbation</measure>
    <time_frame>Participants will be followed for the duration of the study, an expected average of 3 weeks</time_frame>
    <description>An asthma exacerbation incident is defined as significant worsening of clinical symptoms that cannot be adequately relieved by the rescue medication, or significant deterioration of FEV1 tests combined with clinical symptoms. Investigators monitor worsening of asthma symptoms during the treatment period and determine if subjects had experienced an asthma exacerbation.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects that Used Rescue Drug</measure>
    <time_frame>Within 30 minutes prior to dosing (baseline) to 6 hours post-dose</time_frame>
    <description>Rescue medication may be used to control worsening or exacerbations of asthma symptoms during the study visits when necessary, as determined by the investigator.</description>
  </other_outcome>
  <other_outcome>
    <measure>Complete Blood Count (CBC) at Screening</measure>
    <time_frame>Within 1 hour after reversibility dosing</time_frame>
    <description>A CBC is performed as part of the subject safety evaluations with differentials including: red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and white blood cell types (WBC).</description>
  </other_outcome>
  <other_outcome>
    <measure>Complete Blood Count (CBC) at End-of-Study</measure>
    <time_frame>120 minutes post-dose at Visit 5 (within 57 days after Visit 1)</time_frame>
    <description>A CBC is performed as part of the subject safety evaluations with differentials including: red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and white blood cell types (WBC).</description>
  </other_outcome>
  <other_outcome>
    <measure>Comprehensive Metabolic Panel (CMP) at Screening</measure>
    <time_frame>Within 1 hour after reversibility dosing</time_frame>
    <description>A CMP is performed as part of the subject safety evaluations looking at levels for the following: total protein (albumin/globulin), sodium, chloride, potassium, glucose, calcium, carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine, alkaline phosphate (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin.</description>
  </other_outcome>
  <other_outcome>
    <measure>Comprehensive Metabolic Panel (CMP) at End-of-Study</measure>
    <time_frame>120 minutes post-dose at Visit 5 (within 57 days after Visit 1)</time_frame>
    <description>A CMP is performed as part of the subject safety evaluations looking at levels for the following: total protein (albumin/globulin), sodium, chloride, potassium, glucose, calcium, carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine, alkaline phosphate (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin.</description>
  </other_outcome>
  <other_outcome>
    <measure>Urinalysis at Screening</measure>
    <time_frame>Within 1 hour after reversibility dosing</time_frame>
    <description>Routine and microscopic urinalysis is performed as part of the subject safety evaluations to measure urine pH and specific gravity.</description>
  </other_outcome>
  <other_outcome>
    <measure>Urinalysis at End-of-Study</measure>
    <time_frame>120 minutes post-dose at Visit 5 (within 57 days after Visit 1)</time_frame>
    <description>Routine and microscopic urinalysis is performed as part of the subject safety evaluations to measure urine pH and specific gravity.</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidents of Pregnancy at Screening</measure>
    <time_frame>Within 1 hour prior to reversibility dosing</time_frame>
    <description>A urinary pregnancy test was performed for women of child-bearing potential as a part of the Screening Visit evaluations to determine the eligibility of the subject for the study.</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidents of Pregnancy at End-of-Study</measure>
    <time_frame>At or after 120 minutes post-dose at Visit 5 (within 57 days after Visit 1)</time_frame>
    <description>A urinary pregnancy test was performed for women of child-bearing potential as a part of the End-of-Study safety evaluations to determine if a pregnancy had occurred during the study.</description>
  </other_outcome>
  <other_outcome>
    <measure>Concomitant Medication Usage</measure>
    <time_frame>Participants will be followed for the duration of the study, an expected average of 3 weeks</time_frame>
    <description>Concomitant medications used by subjects throughout the duration of the study, from 30 days prior to Screening to End-of-Study evaluations, are recorded by the investigators. The total number of times a specific concomitant medication is used during the study is summarized.</description>
  </other_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Treatment T1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One inhalation of 110 mcg A006 DPI. Total 110 mcg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment T2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One inhalation of 220 mcg A006 DPI. Total 220 mcg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>One inhalation of placebo DPI . Total 0 mcg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment R1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One inhalation of Proventil® MDI Total 90 mcg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment R2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Two inhalations of Proventil® MDI, 180 mcg total</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>A006 DPI</intervention_name>
    <description>Single dose 110 mcg, 1 inhalation</description>
    <arm_group_label>Treatment T1</arm_group_label>
    <other_name>Albuterol</other_name>
    <other_name>Albuterol DPI</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>A006 DPI</intervention_name>
    <description>Single dose 220 mcg, 1 inhalation</description>
    <arm_group_label>Treatment T2</arm_group_label>
    <other_name>Albuterol</other_name>
    <other_name>Albuterol DPI</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo DPI</intervention_name>
    <description>Placebo, 1 inhalation</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Proventil® MDI</intervention_name>
    <description>Single dose 90 mcg, 1 inhalation</description>
    <arm_group_label>Treatment R1</arm_group_label>
    <other_name>Proventil®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Proventil® MDI</intervention_name>
    <description>Single dose 90 mcg, 2 inhalations</description>
    <arm_group_label>Treatment R2</arm_group_label>
    <other_name>Proventil®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Generally healthy, male and female adults, 18-55 years of age at Screening&#xD;
&#xD;
          -  With mild-to-moderate persistent asthma for at least 6 months prior to Screening, and&#xD;
             having used inhaled β-agonist(s) for asthma control&#xD;
&#xD;
          -  Demonstrating a Screening Baseline FEV1 at 50.0 - 85.0% of predicted normal&#xD;
&#xD;
          -  Demonstrating a ≥ 15.0% Airway Reversibility in FEV1 within 30 min after inhaling 2&#xD;
             actuations of Proventil® MDI (180 mcg) at Screening&#xD;
&#xD;
          -  Demonstrating Peak Inspiratory Flow Rate (PIF) within 80-150 L/min (after training),&#xD;
             for at least 2 times consecutively with a maximum of 5 attempts&#xD;
&#xD;
          -  Demonstrating proficiency in the use of a DPI and an MDI after training&#xD;
&#xD;
          -  Females of child-bearing potential must be non-pregnant, non-lactating; both males and&#xD;
             females enrolled into the study must agree to practice a clinically acceptable form of&#xD;
             birth control (including but not limited to, abstinence, double barrier, etc)&#xD;
&#xD;
          -  Having properly consented to participate in the trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A smoking history of ≥ 5 pack-years, or having smoked within 6 months prior to&#xD;
             Screening&#xD;
&#xD;
          -  Upper respiratory tract infections or lower respiratory tract infection within 6&#xD;
             weeks, prior to Screening&#xD;
&#xD;
          -  Asthma exacerbations that required emergency care or hospitalized treatment, within 4&#xD;
             weeks prior to Screening&#xD;
&#xD;
          -  Any current or recent respiratory conditions that, per investigator discretion, might&#xD;
             significantly affect pharmacodynamic response to the study drugs, including cystic&#xD;
             fibrosis, bronchiectasis, tuberculosis, emphysema, and other significant respiratory&#xD;
             diseases besides asthma&#xD;
&#xD;
          -  Concurrent clinically significant cardiovascular (e.g. hypertension and&#xD;
             tachyarrhythmia and bradyarrhythmia), hematological, renal, neurologic, hepatic,&#xD;
             endocrine, psychiatric, malignant, or other illnesses that in the opinion of the&#xD;
             investigator could impact on the conduct, safety and evaluation of the study&#xD;
&#xD;
          -  Known intolerance or hypersensitivity to any of the ingredients of the study drug DPI&#xD;
             or Proventil® HFA MDI (i.e., Albuterol, sulfate, lactose, milk protein, HFA-134a,&#xD;
             oleic acid, and ethanol)&#xD;
&#xD;
          -  Baseline ECG at Screening or Visit 1 showing any single or multiple premature&#xD;
             ventricular contractions (PVC)&#xD;
&#xD;
          -  Baseline ECG at Screening or Visit 1 with a confirmed (through performing a second&#xD;
             ECG) QTc reading greater than 450ms&#xD;
&#xD;
          -  Use of prohibited drugs or failure to observe the drug washout restrictions&#xD;
&#xD;
          -  Having been on other clinical drug/device studies in the last 30 days prior to&#xD;
             Screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Safety Monitor</last_name>
    <role>Study Director</role>
    <affiliation>Amphastar Pharmeceuticals, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Amphastar Site 0001</name>
      <address>
        <city>San Jose</city>
        <state>California</state>
        <zip>95117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Amphastar Site 0025</name>
      <address>
        <city>Medford</city>
        <state>Oregon</state>
        <zip>97504</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Amphastar Site 0030</name>
      <address>
        <city>New Braunfels</city>
        <state>Texas</state>
        <zip>78130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Amphastar Site 0032</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Lipworth BJ, Clark DJ. Lung delivery of salbutamol given by breath activated pressurized aerosol and dry powder inhaler devices. Pulm Pharmacol Ther. 1997 Aug;10(4):211-4. doi: 10.1006/pupt.1997.0093.</citation>
    <PMID>9695144</PMID>
  </reference>
  <reference>
    <citation>Ahrens RC. The role of the MDI and DPI in pediatric patients: &quot;Children are not just miniature adults&quot;. Respir Care. 2005 Oct;50(10):1323-8; discussion 1328-30.</citation>
    <PMID>16185368</PMID>
  </reference>
  <reference>
    <citation>Goldstein DA, Tan YK, Soldin SJ. Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers. Eur J Clin Pharmacol. 1987;32(6):631-4. doi: 10.1007/BF02456001.</citation>
    <PMID>3653233</PMID>
  </reference>
  <reference>
    <citation>Hindle M, Newton DA, Chrystyn H. Dry powder inhalers are bioequivalent to metered-dose inhalers. A study using a new urinary albuterol (salbutamol) assay technique. Chest. 1995 Mar;107(3):629-33. doi: 10.1378/chest.107.3.629.</citation>
    <PMID>7874928</PMID>
  </reference>
  <reference>
    <citation>Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. Interpretative strategies for lung function tests. Eur Respir J. 2005 Nov;26(5):948-68. doi: 10.1183/09031936.05.00035205. No abstract available.</citation>
    <PMID>16264058</PMID>
  </reference>
  <reference>
    <citation>Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981 Jun;123(6):659-64. doi: 10.1164/arrd.1981.123.6.659.</citation>
    <PMID>7271065</PMID>
  </reference>
  <reference>
    <citation>Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir. 1982 May-Jun;18(3):419-25.</citation>
    <PMID>7074238</PMID>
  </reference>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>August 4, 2014</study_first_submitted>
  <study_first_submitted_qc>August 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 7, 2014</study_first_posted>
  <disposition_first_submitted>April 17, 2017</disposition_first_submitted>
  <disposition_first_submitted_qc>April 17, 2017</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">April 19, 2017</disposition_first_posted>
  <last_update_submitted>April 17, 2017</last_update_submitted>
  <last_update_submitted_qc>April 17, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Asthma</keyword>
  <keyword>Mild-to-moderate persistent asthma</keyword>
  <keyword>Mild asthma</keyword>
  <keyword>Moderate asthma</keyword>
  <keyword>Persistent asthma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Albuterol</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT02210806
org study id: API-A006-CL-B3
nct id: NCT02210806
lead sponsor: 
has dmc: No
This study evaluates the efficacy, dose-ranging and safety profiles of A006, an Albuterol dry
      powder inhaler (DPI), in the dose range of 110 to 220 mcg per dose in comparison to a DPI
      Placebo Control and an Albuterol metered dose inhaler (MDI) Active Control.
This study is designed to evaluate the efficacy and safety profiles of A006 and to assist in
      identifying the optimum dose of A006 for future clinical studies. Proventil® HFA MDI, a
      currently marketed Albuterol MDI product, will be used as an Active Control. The study also
      employs a Placebo Control DPI, which has the same configuration as the A006 DPI except that
      it contains no active ingredient.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 Percentage Change (∆%FEV1) from the Same-Day Pre-Dose Baseline
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule. Statistical analysis is performed using a one-sided t-test.
measure: Area Under the Curve (AUC[0-6h]) of Placebo Adjusted Post-Dose FEV1 Percentage Change (∆∆%FEV1) from the Same-Day Pre-Dose Baseline
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. ∆∆FEV1% for the study visit is calculated by subtracting the mean ∆%FEV1 for subjects in a randomized treatment arm from their ∆%FEV1. Area under the curve (AUC), from baseline to 6 hours post-dose, for the study visit is calculated using the trapezoidal rule.
measure: Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 Volume Changes (∆FEV1) from the Same-Day Pre-Dose Baseline
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule.
measure: Time to Onset of Bronchodilator Effect (t[onset])
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. t[onset] is the point where post-dose ∆%FEV1 first reaches ≥ 12% over the pre-dose baseline. Determined by linear interpolation.
measure: Peak Bronchodilator Response (F[max])
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. F[max] is the maximum post-dose ∆%FEV1.
measure: Time to Peak ∆FEV1 Effect (t[max])
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. The time to peak ∆FEV1 effect, t[max], is defined as the time of F[max].
measure: Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 in Volume from the Same-Day Pre-Dose Baseline
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule.
measure: F[max] of Post-Dose FEV1 in Volume
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. F[max] of post-dose FEV1 in volume is the maximum post-dose FEV1.
measure: Efficacy Duration-1
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-1 is total duration of bronchodilator effects when ∆%FEV1 is ≥ 12% above the baseline.
measure: Efficacy Duration-2
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-2 is total duration of bronchodilator effects when ∆FEV1 is ≥ 200 mL above the baseline.
measure: Efficacy Duration-3
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-3 is total duration of bronchodilator effects when ∆FEV1 is ≥ 100 mL above the baseline.
measure: Bronchodilator Response
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Subjects that demonstrate a ≥ 12% increase for ∆%FEV1 will be classified as having a bronchodilator response.
measure: Dose Response Curve
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. The dose response curve is the AUC[0-6h] of ∆%FEV1 versus study drug dosage.
measure: Systolic and Diastolic Blood Pressure (SBP/DBP) at Screening
time frame: Within 30 minutes prior to reversibility dosing (baseline) and 30 minutes post-reversibility dosing
description: Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to reversibility dosing and 30 minutes after dosing during the Screening Visit.
measure: Systolic and Diastolic Blood Pressure (SBP/DBP)
time frame: Within 1 hour prior to dosing (baseline) to 6 hours post-dose
description: Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at 15 and 30 minutes and 1, 1.5, 2, and 6 hours post-dose during each treatment period.
measure: Heart Rate (HR) at Screening
time frame: Within 30 minutes prior to reversibility dosing (baseline) and 30 minutes post-reversibility dosing
description: Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to reversibility dosing and 30 minutes after dosing during the Screening Visit.
measure: Heart Rate (HR)
time frame: Within 1 hour prior to dosing (baseline) to 6 hours post-dose
description: Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at 15 and 30 minutes and 1, 1.5, 2, and 6 hours post-dose during each treatment period.
measure: 12-Lead ECG QT/QTc Intervals at Screening
time frame: Within 1 hour prior to reversibility dosing
description: 12-Lead ECGs are performed to measure QT and QTc intervals prior to reversibility dosing during the Screening Visit.
measure: 12-Lead ECG QT/QTc Intervals
time frame: Within 1 hour prior to dosing (baseline) to 6 hours post-dose
description: 12-Lead ECGs are performed to measure QT and QTc intervals prior to dosing and at 30 minutes and 1, 2, and 6 hours post-dose during each treatment period.
measure: Number of Subjects with Incidents of Asthma Exacerbation
time frame: Participants will be followed for the duration of the study, an expected average of 3 weeks
description: An asthma exacerbation incident is defined as significant worsening of clinical symptoms that cannot be adequately relieved by the rescue medication, or significant deterioration of FEV1 tests combined with clinical symptoms. Investigators monitor worsening of asthma symptoms during the treatment period and determine if subjects had experienced an asthma exacerbation.
measure: Number of Subjects that Used Rescue Drug
time frame: Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
description: Rescue medication may be used to control worsening or exacerbations of asthma symptoms during the study visits when necessary, as determined by the investigator.
measure: Complete Blood Count (CBC) at Screening
time frame: Within 1 hour after reversibility dosing
description: A CBC is performed as part of the subject safety evaluations with differentials including: red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and white blood cell types (WBC).
measure: Complete Blood Count (CBC) at End-of-Study
time frame: 120 minutes post-dose at Visit 5 (within 57 days after Visit 1)
description: A CBC is performed as part of the subject safety evaluations with differentials including: red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and white blood cell types (WBC).
measure: Comprehensive Metabolic Panel (CMP) at Screening
time frame: Within 1 hour after reversibility dosing
description: A CMP is performed as part of the subject safety evaluations looking at levels for the following: total protein (albumin/globulin), sodium, chloride, potassium, glucose, calcium, carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine, alkaline phosphate (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin.
measure: Comprehensive Metabolic Panel (CMP) at End-of-Study
time frame: 120 minutes post-dose at Visit 5 (within 57 days after Visit 1)
description: A CMP is performed as part of the subject safety evaluations looking at levels for the following: total protein (albumin/globulin), sodium, chloride, potassium, glucose, calcium, carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine, alkaline phosphate (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin.
measure: Urinalysis at Screening
time frame: Within 1 hour after reversibility dosing
description: Routine and microscopic urinalysis is performed as part of the subject safety evaluations to measure urine pH and specific gravity.
measure: Urinalysis at End-of-Study
time frame: 120 minutes post-dose at Visit 5 (within 57 days after Visit 1)
description: Routine and microscopic urinalysis is performed as part of the subject safety evaluations to measure urine pH and specific gravity.
measure: Incidents of Pregnancy at Screening
time frame: Within 1 hour prior to reversibility dosing
description: A urinary pregnancy test was performed for women of child-bearing potential as a part of the Screening Visit evaluations to determine the eligibility of the subject for the study.
measure: Incidents of Pregnancy at End-of-Study
time frame: At or after 120 minutes post-dose at Visit 5 (within 57 days after Visit 1)
description: A urinary pregnancy test was performed for women of child-bearing potential as a part of the End-of-Study safety evaluations to determine if a pregnancy had occurred during the study.
measure: Concomitant Medication Usage
time frame: Participants will be followed for the duration of the study, an expected average of 3 weeks
description: Concomitant medications used by subjects throughout the duration of the study, from 30 days prior to Screening to End-of-Study evaluations, are recorded by the investigators. The total number of times a specific concomitant medication is used during the study is summarized.
arm group label: Treatment T1
arm group type: Active Comparator
description: One inhalation of 110 mcg A006 DPI. Total 110 mcg.
arm group label: Treatment T2
arm group type: Active Comparator
description: One inhalation of 220 mcg A006 DPI. Total 220 mcg.
arm group label: Placebo
arm group type: Placebo Comparator
description: One inhalation of placebo DPI . Total 0 mcg
arm group label: Treatment R1
arm group type: Active Comparator
description: One inhalation of Proventil® MDI Total 90 mcg
arm group label: Treatment R2
arm group type: Active Comparator
description: Two inhalations of Proventil® MDI, 180 mcg total
intervention type: Drug
intervention name: A006 DPI
description: Single dose 110 mcg, 1 inhalation
arm group label: Treatment T1
other name: Albuterol
other name: Albuterol DPI
intervention type: Drug
intervention name: A006 DPI
description: Single dose 220 mcg, 1 inhalation
arm group label: Treatment T2
other name: Albuterol
other name: Albuterol DPI
intervention type: Other
intervention name: Placebo DPI
description: Placebo, 1 inhalation
arm group label: Placebo
other name: Placebo
intervention type: Drug
intervention name: Proventil® MDI
description: Single dose 90 mcg, 1 inhalation
arm group label: Treatment R1
other name: Proventil®
intervention type: Drug
intervention name: Proventil® MDI
description: Single dose 90 mcg, 2 inhalations
arm group label: Treatment R2
other name: Proventil®
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: No
last name: Safety Monitor
role: Study Director
affiliation: Amphastar Pharmeceuticals, Inc.
facility: 
facility: 
facility: 
facility: 
country: United States
citation: Lipworth BJ, Clark DJ. Lung delivery of salbutamol given by breath activated pressurized aerosol and dry powder inhaler devices. Pulm Pharmacol Ther. 1997 Aug;10(4):211-4. doi: 10.1006/pupt.1997.0093.
PMID: 9695144
citation: Ahrens RC. The role of the MDI and DPI in pediatric patients: "Children are not just miniature adults". Respir Care. 2005 Oct;50(10):1323-8; discussion 1328-30.
PMID: 16185368
citation: Goldstein DA, Tan YK, Soldin SJ. Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers. Eur J Clin Pharmacol. 1987;32(6):631-4. doi: 10.1007/BF02456001.
PMID: 3653233
citation: Hindle M, Newton DA, Chrystyn H. Dry powder inhalers are bioequivalent to metered-dose inhalers. A study using a new urinary albuterol (salbutamol) assay technique. Chest. 1995 Mar;107(3):629-33. doi: 10.1378/chest.107.3.629.
PMID: 7874928
citation: Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. Interpretative strategies for lung function tests. Eur Respir J. 2005 Nov;26(5):948-68. doi: 10.1183/09031936.05.00035205. No abstract available.
PMID: 16264058
citation: Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981 Jun;123(6):659-64. doi: 10.1164/arrd.1981.123.6.659.
PMID: 7271065
citation: Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir. 1982 May-Jun;18(3):419-25.
PMID: 7074238
responsible party type: Sponsor
mesh term: Asthma
mesh term: Albuterol