<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/NCT04440488</url>
  </required_header>
  <id_info>
    <org_study_id>TAK-883-3001</org_study_id>
    <nct_id>NCT04440488</nct_id>
  </id_info>
  <brief_title>ARALAST NP Alpha-1 Lung Density Chronic Obstructive Pulmonary Disease-Emphysema (COPD-E) Study</brief_title>
  <official_title>A Prospective, Randomized, Double-Blind, Parallel Group Study to Evaluate the Safety and Efficacy of ARALAST NP 60 mg/kg and 120 mg/kg for Alpha-1 Proteinase Inhibitor (A1PI) Augmentation Therapy in Subjects With A1PI Deficiency and Chronic Obstructive Pulmonary Disease-Emphysema (COPD-E)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shire</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Takeda</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the efficacy of ARALAST NP A1PI augmentation therapy&#xD;
      120 milligrams per kilogram (mg/kg) body weight (BW)/week compared with an external placebo&#xD;
      comparator on the loss of emphysematous lung tissue measured by lung density change in&#xD;
      participants with A1PI deficiency and COPD-E.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Reevaluation of development strategy&#xD;
  </why_stopped>
  <start_date type="Anticipated">March 8, 2021</start_date>
  <completion_date type="Anticipated">September 12, 2025</completion_date>
  <primary_completion_date type="Anticipated">September 12, 2025</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Annual Rate of the Physiologically Adjusted Lung Density Change</measure>
    <time_frame>Baseline, up to Week 104</time_frame>
    <description>Annual rate of the physiologically adjusted lung density change will be measured as the 15th percentile of the lung density measurements (PD15) as assessed by Computed Tomography (CT) densitometry at total lung capacity (TLC). CT lung density at the 15th percentile (PD15) is the threshold below which 15 percentage (%) of the voxels have lower densities and is used as the parameter for estimating the rate of lung density decline. Annual rate of the physiologically adjusted lung density change will be tested in a fixed comparision sequence 1. ARALAST NP 120 mg/kg BW/week group versus (vs) external placebo group, 2. ARALAST NP120 mg/kg BW/week vs 60 mg/kg BW/week, 3. ARALAST NP 60 mg/kg BW/week group vs external placebo group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Moderate or Severe Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)</measure>
    <time_frame>Baseline, up to Week 104</time_frame>
    <description>COPD exacerbations are defined as an acute worsening of respiratory symptoms that results in additional therapy and will be assessed according to the classification in GOLD criteria (2020) as follows: Moderate (treated with short acting bronchodilators [SABDs] plus antibiotics and/or oral corticosteroids) and Severe (required hospitalizations or a visit to the emergency room).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Annual Rate of Change in Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)</measure>
    <time_frame>Baseline, up to Week 104</time_frame>
    <description>Annual rate of change in post-bronchodilator FEV1 will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Treatment-Emergent Adverse Events (TEAE's)</measure>
    <time_frame>From Start of the study drug administration up to End of the study (up to Week 105)</time_frame>
    <description>An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this IP or medicinal product. A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with an IP or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. TEAE's will include related, serious adverse events (SAEs), suspected adverse reactions plus adverse reactions of interest, temporally-associated adverse events (AEs) with onset during infusion or within 24 hours following the end of IP infusion, and AEs resulting in changes to infusion dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Who Develop Anti-A1PI Antibodies Following Treatment With ARALAST NP</measure>
    <time_frame>From Start of the study drug administration up to End of the study (up to Week 105)</time_frame>
    <description>Number of participants who develop anti- A1PI antibodies following treatment with ARALAST NP will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Trough Level of Antigenic and Functional A1PI for ARALAST NP at each dose Level</measure>
    <time_frame>Pre-dose, Weeks 4, 13, 28, 52, 78, 91, 104, 105</time_frame>
    <description>Plasma trough level of antigenic and functional A1PI for ARALAST NP at each dose level (ARALAST NP 60 mg/kg BW/week, ARALAST NP 120 mg/kg BW/week) will be assessed.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <condition>Alpha1-antitrypsin Deficiency</condition>
  <arm_group>
    <arm_group_label>ARALAST NP 120 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive 120 mg/kg BW of ARALAST NP intravenous (IV) infusion once in a week for a total of 104 weeks which will be compared with an external placebo arm.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ARALAST NP 60 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive 60 mg/kg BW of ARALAST NP IV infusion once in a week for a total of 104 weeks which will be compared with an external placebo arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ARALAST NP</intervention_name>
    <description>Partcipants will be randomized to receive ARALAST NP 60 or 120 mg/kg BW/week IV infusion for a total of 104 weeks.</description>
    <arm_group_label>ARALAST NP 120 mg/kg</arm_group_label>
    <arm_group_label>ARALAST NP 60 mg/kg</arm_group_label>
    <other_name>Alpha1-PI</other_name>
    <other_name>TAK-883</other_name>
    <other_name>A1PI</other_name>
    <other_name>Alpha1-Proteinase Inhibitor (Human)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults 18 to 65 years of age at the time of screening&#xD;
&#xD;
          -  Diagnosis of A1PI deficiency with endogenous plasma A1PI level less than (&lt;) 11&#xD;
             micromoles(μM) (&lt; 0598 milligram per milliliter [mg/mL]) following 4-week minimum&#xD;
             washout from previous last dose of A1PI augmentation therapy The screening plasma A1PI&#xD;
             level may be repeated if a participant is determined to have an exclusionary value&#xD;
             that maybe due to an inadequate washout of augmentation therapy Participants eligible&#xD;
             for enrollment include newly diagnosed, previously untreated, currently treated and&#xD;
             currently not on treatment but received treatment in the past&#xD;
&#xD;
          -  Participants should have a documented A1PI genotype and if not, A1PI genotyping will&#xD;
             be offered at the time of screening The purpose for genotyping is for sub-group&#xD;
             analysis of study results only&#xD;
&#xD;
          -  Clinically evident COPD-E (according to GOLD criteria (2020) for diagnosis, Stage&#xD;
             I-III) (Global Initiative for Chronic Obstructive Lung Disease [COPD]) at the time of&#xD;
             screening defined as follows: Forced expiratory volume in 1 second (FEV1) is greater&#xD;
             than or equal to (&gt;or=) 35% and less than or equal to (&lt;or=) 70% predicted&#xD;
&#xD;
          -  If treated with any respiratory medications including inhaled bronchodilators, inhaled&#xD;
             corticosteroids, or systemic corticosteroids (example [eg] prednisone &lt;or= 10&#xD;
             milligram per day [mg/day] or its equivalent), the doses of medications should have&#xD;
             remained stable for at least 28 days prior to screening&#xD;
&#xD;
          -  No clinically significant abnormalities (other than emphysema, bronchitis or&#xD;
             bronchiectasis) detected via chest CT at the time of screening&#xD;
&#xD;
          -  Males and non-pregnant, non-lactating females whose screening pregnancy test is&#xD;
             negative and willing and able to employ adequate contraceptive methods deemed reliable&#xD;
             by the investigator for the duration of the study&#xD;
&#xD;
          -  Willing and able to refrain from smoking (including e-cigarettes and vaping of any&#xD;
             other substance) for the duration of study&#xD;
&#xD;
          -  Willing and able to comply with the requirements of the protocol and able to&#xD;
             voluntarily provide written, signed, and dated (personally or via a legally authorized&#xD;
             representative) an informed consent to participate in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known ongoing or history of clinically significant disease other than respiratory or&#xD;
             liver disease secondary to AATD&#xD;
&#xD;
          -  If experiencing corona virus diease (COVID)-19, lower respiratory tract infection&#xD;
             (LRTI) and/or acute COPD exacerbation at the time of screening. Participant may be&#xD;
             re-screened after clinical resolution of COVID-19, LRTI and/or acute COPD exacerbation&#xD;
             and having also remained stable for at least 6 weeks after resolution&#xD;
&#xD;
          -  Known ongoing or history of clinically significant cor pulmonale and/or congestive&#xD;
             heart failure with New York Heart Association (NYHA) Class III/IV symptoms&#xD;
&#xD;
          -  Has received an organ transplant, has undergone major lung surgery (eg, lung volume&#xD;
             reduction surgery or lobectomy surgery), or is currently on a transplant waiting list&#xD;
&#xD;
          -  Known history of ongoing malignancy (other than adequately treated basal cell or&#xD;
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix, or stable&#xD;
             prostate cancer not requiring treatment)&#xD;
&#xD;
          -  Current active smoker (including e-cigarettes or vaping, nicotine or any other&#xD;
             substance). A participant with a previous history of smoking has to have ceased active&#xD;
             smoking at least 6 months prior to screening. Participants with a positive&#xD;
             nicotine/cotinine test due to nicotine replacement therapy (eg, patches, chewing gum)&#xD;
             or snuff are eligible&#xD;
&#xD;
          -  Receiving long-term therapy (&gt; 28 days) of parenteral corticosteroids or oral&#xD;
             corticosteroids at doses greater than 10 mg/day of prednisone or its equivalent&#xD;
&#xD;
          -  Receiving chronic 24 hours/day oxygen supplementation (other than for an acute COPD&#xD;
             exacerbation, or supplemental oxygen with continuous positive airway pressure [CPAP],&#xD;
             or bi-level positive airway pressure [BiPAP] for acute respiratory failure)&#xD;
&#xD;
          -  Known selective immunoglobulin A (IgA) deficiency (IgA level &lt; 7 milligrams per&#xD;
             deciliter [mg/dL] at screening) with anti-IgA antibodies and a history of&#xD;
             hypersensitivity reaction&#xD;
&#xD;
          -  Known history of hypersensitivity following infusions of human immunoglobulins, human&#xD;
             albumin, blood or blood components&#xD;
&#xD;
          -  Presence of clinically significant laboratory abnormalities at the screening that in&#xD;
             the opinion of the investigator would impact the participant's safety, if enrolled in&#xD;
             the study&#xD;
&#xD;
          -  Presence of any of the following that in the opinion of the investigator, would affect&#xD;
             participant's safety or compliance or confound the results of the study, including&#xD;
             known clinically significant medical, psychiatric, or cognitive illness, is a&#xD;
             recreational drug/alcohol user, or has any other uncontrolled medical condition (eg,&#xD;
             unstable angina, transient ischemic attack, uncontrolled hypertension)&#xD;
&#xD;
          -  Known exposure to another IP within 28 days prior to enrollment or is scheduled to&#xD;
             participate in another clinical study involving an IP or investigational device during&#xD;
             the course of this study&#xD;
&#xD;
          -  Participant is a family member or employee of the investigator&#xD;
&#xD;
          -  If female, participant is pregnant or nursing at the time of enrollment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Shire</affiliation>
  </overall_official>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>June 17, 2020</study_first_submitted>
  <study_first_submitted_qc>June 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 19, 2020</study_first_posted>
  <last_update_submitted>September 10, 2020</last_update_submitted>
  <last_update_submitted_qc>September 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alpha 1-Antitrypsin Deficiency</mesh_term>
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Emphysema</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Protease Inhibitors</mesh_term>
    <mesh_term>Alpha 1-Antitrypsin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_access_criteria>IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.</ipd_access_criteria>
    <ipd_url>https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT04440488
org study id: TAK-883-3001
nct id: NCT04440488
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to evaluate the efficacy of ARALAST NP A1PI augmentation therapy
      120 milligrams per kilogram (mg/kg) body weight (BW)/week compared with an external placebo
      comparator on the loss of emphysematous lung tissue measured by lung density change in
      participants with A1PI deficiency and COPD-E.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Annual Rate of the Physiologically Adjusted Lung Density Change
time frame: Baseline, up to Week 104
description: Annual rate of the physiologically adjusted lung density change will be measured as the 15th percentile of the lung density measurements (PD15) as assessed by Computed Tomography (CT) densitometry at total lung capacity (TLC). CT lung density at the 15th percentile (PD15) is the threshold below which 15 percentage (%) of the voxels have lower densities and is used as the parameter for estimating the rate of lung density decline. Annual rate of the physiologically adjusted lung density change will be tested in a fixed comparision sequence 1. ARALAST NP 120 mg/kg BW/week group versus (vs) external placebo group, 2. ARALAST NP120 mg/kg BW/week vs 60 mg/kg BW/week, 3. ARALAST NP 60 mg/kg BW/week group vs external placebo group.
measure: Number of Moderate or Severe Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)
time frame: Baseline, up to Week 104
description: COPD exacerbations are defined as an acute worsening of respiratory symptoms that results in additional therapy and will be assessed according to the classification in GOLD criteria (2020) as follows: Moderate (treated with short acting bronchodilators [SABDs] plus antibiotics and/or oral corticosteroids) and Severe (required hospitalizations or a visit to the emergency room).
measure: Annual Rate of Change in Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
time frame: Baseline, up to Week 104
description: Annual rate of change in post-bronchodilator FEV1 will be assessed.
measure: Number of Participants with Treatment-Emergent Adverse Events (TEAE's)
time frame: From Start of the study drug administration up to End of the study (up to Week 105)
description: An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this IP or medicinal product. A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with an IP or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. TEAE's will include related, serious adverse events (SAEs), suspected adverse reactions plus adverse reactions of interest, temporally-associated adverse events (AEs) with onset during infusion or within 24 hours following the end of IP infusion, and AEs resulting in changes to infusion dose.
measure: Number of Participants Who Develop Anti-A1PI Antibodies Following Treatment With ARALAST NP
time frame: From Start of the study drug administration up to End of the study (up to Week 105)
description: Number of participants who develop anti- A1PI antibodies following treatment with ARALAST NP will be assessed.
measure: Plasma Trough Level of Antigenic and Functional A1PI for ARALAST NP at each dose Level
time frame: Pre-dose, Weeks 4, 13, 28, 52, 78, 91, 104, 105
description: Plasma trough level of antigenic and functional A1PI for ARALAST NP at each dose level (ARALAST NP 60 mg/kg BW/week, ARALAST NP 120 mg/kg BW/week) will be assessed.
arm group label: ARALAST NP 120 mg/kg
arm group type: Experimental
description: Participants will receive 120 mg/kg BW of ARALAST NP intravenous (IV) infusion once in a week for a total of 104 weeks which will be compared with an external placebo arm.
arm group label: ARALAST NP 60 mg/kg
arm group type: Experimental
description: Participants will receive 60 mg/kg BW of ARALAST NP IV infusion once in a week for a total of 104 weeks which will be compared with an external placebo arm.
intervention type: Biological
intervention name: ARALAST NP
description: Partcipants will be randomized to receive ARALAST NP 60 or 120 mg/kg BW/week IV infusion for a total of 104 weeks.
arm group label: ARALAST NP 120 mg/kg
arm group label: ARALAST NP 60 mg/kg
other name: Alpha1-PI
other name: TAK-883
other name: A1PI
other name: Alpha1-Proteinase Inhibitor (Human)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Study Director
role: Study Director
affiliation: Shire
responsible party type: Sponsor
mesh term: Alpha 1-Antitrypsin Deficiency
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Emphysema
mesh term: Protease Inhibitors
mesh term: Alpha 1-Antitrypsin
sharing ipd: Yes
ipd description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd access criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
ipd url: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers