<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/NCT03277313</url>
  </required_header>
  <id_info>
    <org_study_id>161503</org_study_id>
    <nct_id>NCT03277313</nct_id>
  </id_info>
  <brief_title>Efficacy, Safety, Tolerability, Immunogenicity and Pharmacokinetic Evaluation of HYQVIA in Pediatric PIDD Subjects</brief_title>
  <official_title>Efficacy, Safety, Tolerability, Immunogenicity and Pharmacokinetic Evaluation of HYQVIA in Pediatric Subjects With Primary Immunodeficiency Diseases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Baxalta now part of Shire</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Baxalta Innovations GmbH, now part of Shire</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Takeda</source>
  <oversight_info>
    <has_dmc>No</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 the study is to acquire additional data on efficacy, safety, tolerability,&#xD;
      immunogenicity, pharmacokinetic (PK) and other parameters of HYQVIA in pediatric (age ≥ 2 to&#xD;
      &lt;16 years) participants with primary immunodeficiency disease (PIDD).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 25, 2017</start_date>
  <completion_date type="Actual">July 20, 2022</completion_date>
  <primary_completion_date type="Actual">July 20, 2022</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of acute serious bacterial infections</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>The rate of acute serious bacterial infections defined as the mean number of acute serious bacterial infections per participant per year.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of all infections</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number of all infections per patient-year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trough levels of immunoglobulin G (IgG) and IgG subclasses</measure>
    <time_frame>Epoch 2, Year 1: Months 0, 6, and 12. Study Epoch 2, Year 2: Months 18, 24, 30, and 36</time_frame>
    <description>Trough levels of immunoglobulin G (IgG) and IgG subclasses for Study Epoch 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trough levels of specific antibodies to clinically relevant pathogens</measure>
    <time_frame>Epoch 2, Study Epoch 2, Year 2: Months 24, and 36</time_frame>
    <description>Clinically relevant pathogens include: Clostridium tetani toxoid, Haemophilus influenzae, and Hepatitis B virus [HBV]) for Study Epoch 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) assessment: Area under the curve (AUC)</measure>
    <time_frame>Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)</time_frame>
    <description>To facilitate comparisons across different dosing intervals (three and four weeks), immunoglobulin G (IgG) exposure (AUC) will be normalized by week.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) assessment: Clearance (CL)</measure>
    <time_frame>Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)</time_frame>
    <description>PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) assessment: maximum concentration (Cmax)</measure>
    <time_frame>Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)</time_frame>
    <description>PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) assessment: minimum concentration (Cmin)</measure>
    <time_frame>Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)</time_frame>
    <description>PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) assessment: time to maximum concentration (Tmax)</measure>
    <time_frame>Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)</time_frame>
    <description>PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) assessment: terminal half-life (T 1/2)</measure>
    <time_frame>Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)</time_frame>
    <description>PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of serious adverse events (SAEs), related and not related</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number of serious adverse events (SAEs) per infusion (excluding infections), related and not related</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of serious adverse events (SAEs), related and not related</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Rate of serious adverse events (SAEs) per infusion (excluding infections), related and not related</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of all adverse events (AEs), related and not related</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number of all adverse events (AEs) per infusion (excluding infections), related and not related</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of all adverse events (AEs), related and not related</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Rate of all adverse events (AEs) per infusion (excluding infections), related and not related</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of local adverse events (AEs), related and not related</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number of local adverse events (AEs) per infusion (excluding infections), related and not related</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of local adverse events (AEs), related and not related</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Rate of local adverse events (AEs) per infusion (excluding infections), related and not related</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of systemic adverse events (AEs), related and not related</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number of systemic adverse events (AEs) per infusion (excluding infections), related and not related</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of systemic adverse events (AEs), related and not related</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Rate of systemic adverse events (AEs) per infusion (excluding infections), related and not related</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of all temporally associated adverse events (AEs) per infusion (excluding infections)</measure>
    <time_frame>From beginning of infusion to 72 hours of completion of infusion.</time_frame>
    <description>Temporally associated AEs are all AEs which begin during the infusion or within 72 hours of completion of infusion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of all temporally associated adverse events (AEs) per infusion (excluding infections)</measure>
    <time_frame>From beginning of infusion to 72 hours of completion of infusion.</time_frame>
    <description>Temporally associated AEs are all AEs which begin during the infusion or within 72 hours of completion of infusion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of all causally related and/or temporally associated adverse events (AEs) per infusion (excluding infections)</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number per infusion (excluding infections) of all causally related and/or temporally associated AEs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of all causally related and/or temporally associated adverse events (AEs) per infusion (excluding infections)</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Rate per infusion (excluding infections) of all causally related and/or temporally associated AEs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rates of all AEs (excluding infections)</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Rates of all AEs (excluding infections) defined as number of AEs categorized by MedDRA preferred terms, seriousness, and severity, divided by the number of infusions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants who develop positive titer of binding or neutralizing antibodies to rHuPH20</measure>
    <time_frame>Epoch 1 (up to 6 weeks) and Epoch 2 (up to 3 years)</time_frame>
    <description>Number of participants who develop positive titer (≥ 160) of binding or neutralizing antibodies to rHuPH20</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of participants who develop positive titer of binding or neutralizing antibodies to rHuPH20</measure>
    <time_frame>Epoch 1 (up to 6 weeks) and Epoch 2 (up to 3 years)</time_frame>
    <description>Percentage of participants who develop positive titer (≥ 160) of binding or neutralizing antibodies to rHuPH20</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of infusions per month</measure>
    <time_frame>Epoch 2 (up to 3 years)</time_frame>
    <description>Median number of infusions per month per participant</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of infusion sites (needle sticks) per infusion/month</measure>
    <time_frame>Epoch 2 (up to 3 years)</time_frame>
    <description>Median number of infusion sites (needle sticks) per infusion/month</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of infusion</measure>
    <time_frame>Epoch 2 (up to 3 years)</time_frame>
    <description>Median duration of infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum infusion rate / site</measure>
    <time_frame>Epoch 2 (up to 3 years)</time_frame>
    <description>Median maximum infusion rate / site</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infusion volume / site</measure>
    <time_frame>Epoch 2 (up to 3 years)</time_frame>
    <description>Median infusion volume / site</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infusions that are discontinued, slowed, or interrupted due to an adverse event (AE)</measure>
    <time_frame>Epoch 2 (up to 3 years)</time_frame>
    <description>Number of infusions that are discontinued, slowed, or interrupted due to an adverse event (AE)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of infusions that are discontinued, slowed, or interrupted due to an adverse event (AE)</measure>
    <time_frame>Epoch 1 (up to 6 weeks) and Epoch 2 (up to 3 years)</time_frame>
    <description>Percentage of infusions that are discontinued, slowed, or interrupted due to an AE</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of weeks to reach final dose interval</measure>
    <time_frame>Epoch 1 (up to 6 weeks)</time_frame>
    <description>Median number of weeks to reach final dose interval (three weeks or four weeks) (Epoch 1)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of participants who achieve a treatment interval of three or four weeks in Epoch 2</measure>
    <time_frame>3 or 4 weeks (dependent on treatment interval)</time_frame>
    <description>Epoch 2: HyQvia treatment at the following intervals: - For intravenous (IV)- pre-treated participants: every three or four weeks, depending on the participant's previous IV dosing schedule. - For subcutaneous (SC) - pre-treated participants: every three or four weeks, a t the discretion of investigator and participant. - For HyQvia pre-treated participants: No change in frequency of administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of participants who maintain a treatment interval of three or four weeks in Epoch 2 for 12 months</measure>
    <time_frame>12 months</time_frame>
    <description>Epoch 2: HyQvia treatment at the following intervals: - For intravenous (IV)- pre-treated participants: every three or four weeks, depending on the participant's previous IV dosing schedule. - For subcutaneous (SC) - pre-treated participants: every three or four weeks, a t the discretion of investigator and participant. - For HyQvia pre-treated participants: No change in frequency of administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life (HRQoL): Pediatric Quality of Life Inventory (Peds-QL)</measure>
    <time_frame>Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36</time_frame>
    <description>The Peds-QL is a generic Health-Related Quality of Life (HRQoL) instrument designed specifically for a pediatric population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life (HRQoL): EuroQol five dimensions questionnaire (EQ-5D)</measure>
    <time_frame>Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36</time_frame>
    <description>EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-case, usual activities, pain/discomfort and anxiety/depression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment Preference and Satisfaction: Assessment of Life Quality Index (LQI)</measure>
    <time_frame>Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36</time_frame>
    <description>The LQI is validated questionnaire assessing patient perceptions of their HRQoL and their treatment specifically among patients who use immunoglobulin therapy. This questionnaire covers 4 domains: Treatment Interferences, Therapy-related Problems, Therapy Setting, and Treatment Costs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment Preference and Satisfaction: Assessment of Treatment Satisfaction and Medication Questionnaire (TSQM-9)</measure>
    <time_frame>Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36</time_frame>
    <description>Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a global satisfaction scale used to assess the overall level of participant's satisfaction or dissatisfaction with their medications.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment Preference and Satisfaction: Assessment of Treatment Preference Questionnaire</measure>
    <time_frame>Epoch 2: months 12, 24, and 36</time_frame>
    <description>The treatment preference questionnaire, internally developed by the study sponsor, is a self-administered, non-validated scale assessing patient preference for various attributes of immunoglobulin G (IgG) therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Resource Utilization: Days not able to go to school or work, or to perform normal daily activities</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Days not able to go to school or work, or to perform normal daily activities due to infection or other illnesses per patient-year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Resource Utilization: Days on antibiotics</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Days on antibiotics per patient-year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Resource Utilization: Number of hospitalizations</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number of hospitalizations, indication for the hospitalization (infection or non-infection)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Resource Utilization: Number of days hospitalized</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number of days hospitalized per patient-year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Resource Utilization: Number of acute physician visits</measure>
    <time_frame>Throughout the study period of approximately six years</time_frame>
    <description>Number of acute physician visits (office and emergency room) due to infection or other illnesses per patient-year</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">44</enrollment>
  <condition>Primary Immunodeficiency Diseases (PID)</condition>
  <arm_group>
    <arm_group_label>Epoch 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pediatric patients with primary immunodeficiency disease (PIDD) who are on intravenous (IV) or non-HYQVIA subcutaneous (SC) treatment with immunoglobulin (IV-pre-treated, SC-pre-treated) will be enrolled and treated with HYQVIA subcutaneously with a dose or interval ramp-up period of up to six weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Epoch 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HYQVIA treatment at following intervals:&#xD;
For intravenous (IV)-pre-treated participants: every 3 or 4 weeks, depending on participant's previous IV schedule.&#xD;
For subcutaneous (SC)-pre-treated participants: every 3 or 4 weeks, at discretion of investigator and participant.&#xD;
After one year in Epoch 2, anti-rHuPH20 binding antibody assay results during year will decide next steps in study:&#xD;
Participants with anti-rHuPH20 antibody titer &lt;160 at all time-points during study will complete the study completion visit at next possible occasion following 12-month visit.&#xD;
Participants with anti-rHuPH20 antibody titer ≥160 during study and/or at last measurement will continue in Epoch 2 for additional 2 years of HYQVIA treatment and observation, and complete study completion visits at next possible occasion following 36-month visit.&#xD;
Alternative treatment intervals, such as infusion every 2 weeks, may be considered for tolerability reasons, at discretion of investigator after informing sponsor</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Epoch 3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Approximately one year safety follow-up, if needed: for participants whose anti-rHuPH20 antibody titer was ≥ 160 during Epoch 1 or Epoch 2 and who experience either a study drug related serious adverse event (SAE) or a related severe adverse event (AE) will be followed accordingly.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>HYQVIA</intervention_name>
    <description>Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with rHuPH20)</description>
    <arm_group_label>Epoch 1</arm_group_label>
    <arm_group_label>Epoch 2</arm_group_label>
    <other_name>IGI 10% with rHuPH20</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>GAMMAGARD LIQUID</intervention_name>
    <description>GAMMAGARD LIQUID IGI (Human), 10% Solution</description>
    <arm_group_label>Epoch 3</arm_group_label>
    <other_name>IGI</other_name>
    <other_name>10%</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Participant must have a documented diagnosis of a form of primary immunodeficiency&#xD;
             (PI) involving a defect in antibody formation and requiring gammaglobulin replacement,&#xD;
             as defined according to the International Union of Immunological Societies (IUIS)&#xD;
             Scientific Committee 2015 (Picard et al., 2015) prior to enrollment. The diagnosis&#xD;
             must be confirmed by the sponsor´s Medical Director prior to first treatment with IP&#xD;
             in the study.&#xD;
&#xD;
          2. Participant is at least two and below 16 years of age at the time of screening.&#xD;
&#xD;
          3. Participant has been receiving a consistent dose of Immunoglobulin G (IgG),&#xD;
             administered in compliance with the respective product information for a period of at&#xD;
             least three months prior to screening. The average minimum pre-study dose over that&#xD;
             interval was equivalent to 300 mg/kg BW / 4 weeks and a maximum dose equivalent to&#xD;
             1000 mg/kg body weight (BW) / 4 weeks.&#xD;
&#xD;
          4. Participant has a serum trough level of IgG &gt; 5 g/L at screening.&#xD;
&#xD;
          5. If female of childbearing potential, participant presents with a negative pregnancy&#xD;
             test and agrees to employ adequate birth control measures for the duration of the&#xD;
             study.&#xD;
&#xD;
          6. Participant /legally authorized representative is willing and able to comply with the&#xD;
             requirements of the protocol.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participant has a known history of or is positive at screening for one or more of the&#xD;
             following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for&#xD;
             hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1/2.&#xD;
&#xD;
          2. Abnormal laboratory values at screening meeting any one of the following criteria&#xD;
             (abnormal tests may be repeated once to determine if they are persistent):&#xD;
&#xD;
               1. Persistent alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &gt;&#xD;
                  2.5 times the upper limit of normal (ULN) for the testing laboratory&#xD;
&#xD;
               2. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] ≤&#xD;
                  500/mm^3)&#xD;
&#xD;
          3. Participant has anemia that would preclude phlebotomy for laboratory studies,&#xD;
             according to standard practice at the site.&#xD;
&#xD;
          4. Participant has an ongoing history of hypersensitivity or persistent reactions&#xD;
             (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following&#xD;
             intravenous (IV) immunoglobulin, subcutaneous (SC) immunoglobulin, and/or Immune Serum&#xD;
             Globulin (ISG) infusions.&#xD;
&#xD;
          5. Participant has severe Immunoglobulin A (IgA) deficiency (less than 7.0 mg/dL) with&#xD;
             known anti-IgA antibodies and a history of hypersensitivity.&#xD;
&#xD;
          6. Participant has a known allergy to hyaluronidase.&#xD;
&#xD;
          7. Participant has active infection and is receiving antibiotic therapy for the treatment&#xD;
             of infection at the time of screening.&#xD;
&#xD;
          8. Participant has a bleeding disorder or a platelet count less than 20,000/μL, or who,&#xD;
             in the opinion of the investigator, would be at significant risk of increased bleeding&#xD;
             or bruising as a result of SC therapy.&#xD;
&#xD;
          9. Participant has severe dermatitis that would preclude adequate sites for safe product&#xD;
             administration in the opinion of the investigator.&#xD;
&#xD;
         10. Participant has participated in another clinical study involving an IP or&#xD;
             investigational device within 30 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;
         11. Participant is a family member or employee of the investigator.&#xD;
&#xD;
         12. If female, participant is pregnant or lactating at the time of enrollment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>15 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>
  <location>
    <facility>
      <name>University of Alabama Medical Center</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Connecticut Children's Medical Center</name>
      <address>
        <city>Hartford</city>
        <state>Connecticut</state>
        <zip>06106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami Pediatric Allergy and Immunology</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of South Florida Physician Group</name>
      <address>
        <city>Saint Petersburg</city>
        <state>Florida</state>
        <zip>33701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Georgia Pollens Clinical Research Centers, Inc.</name>
      <address>
        <city>Albany</city>
        <state>Georgia</state>
        <zip>31707</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory Healthcare</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston Children's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Women &amp; Children's Hospital of Buffalo</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwell Health, Inc. PRIME</name>
      <address>
        <city>Great Neck</city>
        <state>New York</state>
        <zip>11021</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stony Brook Children's Hospital</name>
      <address>
        <city>Stony Brook</city>
        <state>New York</state>
        <zip>11794</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Carolinas Healthcare System</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allergy Asthma &amp; Immunology Relief of Charlotte</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28277</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>OK Institute of Allergy &amp; Asthma Clinical Research, LLC</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73131</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vital Prospects Clinical Research Institute, P.C.</name>
      <address>
        <city>Tulsa</city>
        <state>Oklahoma</state>
        <zip>74136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allergy Partners of North Texas Research</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Section on Immunopathogenesis and Clinical Immunology</name>
      <address>
        <city>Fairfax</city>
        <state>Virginia</state>
        <zip>22030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Marshall University Joan C. Edwards School of Medicine</name>
      <address>
        <city>Charleston</city>
        <state>West Virginia</state>
        <zip>25701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2022</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 11, 2017</study_first_posted>
  <last_update_submitted>September 28, 2022</last_update_submitted>
  <last_update_submitted_qc>September 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 29, 2022</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>Primary Immunodeficiency Diseases</mesh_term>
    <mesh_term>Immunologic Deficiency Syndromes</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunoglobulins, Intravenous</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment 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 on https://vivli.org/ourmember/takeda/. 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://vivli.org/ourmember/takeda/</ipd_url>
  </patient_data>
  <pending_results>
    <submitted>July 12, 2023</submitted>
    <returned>August 2, 2023</returned>
  </pending_results>
  <!-- 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/NCT03277313
org study id: 161503
nct id: NCT03277313
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The purpose of the study is to acquire additional data on efficacy, safety, tolerability,
      immunogenicity, pharmacokinetic (PK) and other parameters of HYQVIA in pediatric (age ≥ 2 to
      <16 years) participants with primary immunodeficiency disease (PIDD).
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Rate of acute serious bacterial infections
time frame: Throughout the study period of approximately six years
description: The rate of acute serious bacterial infections defined as the mean number of acute serious bacterial infections per participant per year.
measure: Number of all infections
time frame: Throughout the study period of approximately six years
description: Number of all infections per patient-year
measure: Trough levels of immunoglobulin G (IgG) and IgG subclasses
time frame: Epoch 2, Year 1: Months 0, 6, and 12. Study Epoch 2, Year 2: Months 18, 24, 30, and 36
description: Trough levels of immunoglobulin G (IgG) and IgG subclasses for Study Epoch 2
measure: Trough levels of specific antibodies to clinically relevant pathogens
time frame: Epoch 2, Study Epoch 2, Year 2: Months 24, and 36
description: Clinically relevant pathogens include: Clostridium tetani toxoid, Haemophilus influenzae, and Hepatitis B virus [HBV]) for Study Epoch 2
measure: Pharmacokinetics (PK) assessment: Area under the curve (AUC)
time frame: Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)
description: To facilitate comparisons across different dosing intervals (three and four weeks), immunoglobulin G (IgG) exposure (AUC) will be normalized by week.
measure: Pharmacokinetics (PK) assessment: Clearance (CL)
time frame: Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)
description: PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.
measure: Pharmacokinetics (PK) assessment: maximum concentration (Cmax)
time frame: Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)
description: PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.
measure: Pharmacokinetics (PK) assessment: minimum concentration (Cmin)
time frame: Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)
description: PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.
measure: Pharmacokinetics (PK) assessment: time to maximum concentration (Tmax)
time frame: Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)
description: PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.
measure: Pharmacokinetics (PK) assessment: terminal half-life (T 1/2)
time frame: Pre-infusion, within one hour of infusion start time. Post-infusion (Day 2- only for participants ≥12 years of age), Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval)
description: PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.
measure: Number of serious adverse events (SAEs), related and not related
time frame: Throughout the study period of approximately six years
description: Number of serious adverse events (SAEs) per infusion (excluding infections), related and not related
measure: Rate of serious adverse events (SAEs), related and not related
time frame: Throughout the study period of approximately six years
description: Rate of serious adverse events (SAEs) per infusion (excluding infections), related and not related
measure: Number of all adverse events (AEs), related and not related
time frame: Throughout the study period of approximately six years
description: Number of all adverse events (AEs) per infusion (excluding infections), related and not related
measure: Rate of all adverse events (AEs), related and not related
time frame: Throughout the study period of approximately six years
description: Rate of all adverse events (AEs) per infusion (excluding infections), related and not related
measure: Number of local adverse events (AEs), related and not related
time frame: Throughout the study period of approximately six years
description: Number of local adverse events (AEs) per infusion (excluding infections), related and not related
measure: Rate of local adverse events (AEs), related and not related
time frame: Throughout the study period of approximately six years
description: Rate of local adverse events (AEs) per infusion (excluding infections), related and not related
measure: Number of systemic adverse events (AEs), related and not related
time frame: Throughout the study period of approximately six years
description: Number of systemic adverse events (AEs) per infusion (excluding infections), related and not related
measure: Rate of systemic adverse events (AEs), related and not related
time frame: Throughout the study period of approximately six years
description: Rate of systemic adverse events (AEs) per infusion (excluding infections), related and not related
measure: Number of all temporally associated adverse events (AEs) per infusion (excluding infections)
time frame: From beginning of infusion to 72 hours of completion of infusion.
description: Temporally associated AEs are all AEs which begin during the infusion or within 72 hours of completion of infusion.
measure: Rate of all temporally associated adverse events (AEs) per infusion (excluding infections)
time frame: From beginning of infusion to 72 hours of completion of infusion.
description: Temporally associated AEs are all AEs which begin during the infusion or within 72 hours of completion of infusion.
measure: Number of all causally related and/or temporally associated adverse events (AEs) per infusion (excluding infections)
time frame: Throughout the study period of approximately six years
description: Number per infusion (excluding infections) of all causally related and/or temporally associated AEs
measure: Rate of all causally related and/or temporally associated adverse events (AEs) per infusion (excluding infections)
time frame: Throughout the study period of approximately six years
description: Rate per infusion (excluding infections) of all causally related and/or temporally associated AEs
measure: Rates of all AEs (excluding infections)
time frame: Throughout the study period of approximately six years
description: Rates of all AEs (excluding infections) defined as number of AEs categorized by MedDRA preferred terms, seriousness, and severity, divided by the number of infusions
measure: Number of participants who develop positive titer of binding or neutralizing antibodies to rHuPH20
time frame: Epoch 1 (up to 6 weeks) and Epoch 2 (up to 3 years)
description: Number of participants who develop positive titer (≥ 160) of binding or neutralizing antibodies to rHuPH20
measure: Percentage of participants who develop positive titer of binding or neutralizing antibodies to rHuPH20
time frame: Epoch 1 (up to 6 weeks) and Epoch 2 (up to 3 years)
description: Percentage of participants who develop positive titer (≥ 160) of binding or neutralizing antibodies to rHuPH20
measure: Number of infusions per month
time frame: Epoch 2 (up to 3 years)
description: Median number of infusions per month per participant
measure: Number of infusion sites (needle sticks) per infusion/month
time frame: Epoch 2 (up to 3 years)
description: Median number of infusion sites (needle sticks) per infusion/month
measure: Duration of infusion
time frame: Epoch 2 (up to 3 years)
description: Median duration of infusion
measure: Maximum infusion rate / site
time frame: Epoch 2 (up to 3 years)
description: Median maximum infusion rate / site
measure: Infusion volume / site
time frame: Epoch 2 (up to 3 years)
description: Median infusion volume / site
measure: Infusions that are discontinued, slowed, or interrupted due to an adverse event (AE)
time frame: Epoch 2 (up to 3 years)
description: Number of infusions that are discontinued, slowed, or interrupted due to an adverse event (AE)
measure: Percentage of infusions that are discontinued, slowed, or interrupted due to an adverse event (AE)
time frame: Epoch 1 (up to 6 weeks) and Epoch 2 (up to 3 years)
description: Percentage of infusions that are discontinued, slowed, or interrupted due to an AE
measure: Number of weeks to reach final dose interval
time frame: Epoch 1 (up to 6 weeks)
description: Median number of weeks to reach final dose interval (three weeks or four weeks) (Epoch 1)
measure: Percentage of participants who achieve a treatment interval of three or four weeks in Epoch 2
time frame: 3 or 4 weeks (dependent on treatment interval)
description: Epoch 2: HyQvia treatment at the following intervals: - For intravenous (IV)- pre-treated participants: every three or four weeks, depending on the participant's previous IV dosing schedule. - For subcutaneous (SC) - pre-treated participants: every three or four weeks, a t the discretion of investigator and participant. - For HyQvia pre-treated participants: No change in frequency of administration
measure: Percentage of participants who maintain a treatment interval of three or four weeks in Epoch 2 for 12 months
time frame: 12 months
description: Epoch 2: HyQvia treatment at the following intervals: - For intravenous (IV)- pre-treated participants: every three or four weeks, depending on the participant's previous IV dosing schedule. - For subcutaneous (SC) - pre-treated participants: every three or four weeks, a t the discretion of investigator and participant. - For HyQvia pre-treated participants: No change in frequency of administration
measure: Health-related Quality of Life (HRQoL): Pediatric Quality of Life Inventory (Peds-QL)
time frame: Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36
description: The Peds-QL is a generic Health-Related Quality of Life (HRQoL) instrument designed specifically for a pediatric population.
measure: Health-related Quality of Life (HRQoL): EuroQol five dimensions questionnaire (EQ-5D)
time frame: Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36
description: EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-case, usual activities, pain/discomfort and anxiety/depression.
measure: Treatment Preference and Satisfaction: Assessment of Life Quality Index (LQI)
time frame: Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36
description: The LQI is validated questionnaire assessing patient perceptions of their HRQoL and their treatment specifically among patients who use immunoglobulin therapy. This questionnaire covers 4 domains: Treatment Interferences, Therapy-related Problems, Therapy Setting, and Treatment Costs.
measure: Treatment Preference and Satisfaction: Assessment of Treatment Satisfaction and Medication Questionnaire (TSQM-9)
time frame: Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36
description: Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a global satisfaction scale used to assess the overall level of participant's satisfaction or dissatisfaction with their medications.
measure: Treatment Preference and Satisfaction: Assessment of Treatment Preference Questionnaire
time frame: Epoch 2: months 12, 24, and 36
description: The treatment preference questionnaire, internally developed by the study sponsor, is a self-administered, non-validated scale assessing patient preference for various attributes of immunoglobulin G (IgG) therapy.
measure: Health Resource Utilization: Days not able to go to school or work, or to perform normal daily activities
time frame: Throughout the study period of approximately six years
description: Days not able to go to school or work, or to perform normal daily activities due to infection or other illnesses per patient-year
measure: Health Resource Utilization: Days on antibiotics
time frame: Throughout the study period of approximately six years
description: Days on antibiotics per patient-year
measure: Health Resource Utilization: Number of hospitalizations
time frame: Throughout the study period of approximately six years
description: Number of hospitalizations, indication for the hospitalization (infection or non-infection)
measure: Health Resource Utilization: Number of days hospitalized
time frame: Throughout the study period of approximately six years
description: Number of days hospitalized per patient-year
measure: Health Resource Utilization: Number of acute physician visits
time frame: Throughout the study period of approximately six years
description: Number of acute physician visits (office and emergency room) due to infection or other illnesses per patient-year
arm group label: Epoch 1
arm group type: Experimental
description: Pediatric patients with primary immunodeficiency disease (PIDD) who are on intravenous (IV) or non-HYQVIA subcutaneous (SC) treatment with immunoglobulin (IV-pre-treated, SC-pre-treated) will be enrolled and treated with HYQVIA subcutaneously with a dose or interval ramp-up period of up to six weeks.
arm group label: Epoch 2
arm group type: Experimental
description: HYQVIA treatment at following intervals:
For intravenous (IV)-pre-treated participants: every 3 or 4 weeks, depending on participant's previous IV schedule.
For subcutaneous (SC)-pre-treated participants: every 3 or 4 weeks, at discretion of investigator and participant.
After one year in Epoch 2, anti-rHuPH20 binding antibody assay results during year will decide next steps in study:
Participants with anti-rHuPH20 antibody titer <160 at all time-points during study will complete the study completion visit at next possible occasion following 12-month visit.
Participants with anti-rHuPH20 antibody titer ≥160 during study and/or at last measurement will continue in Epoch 2 for additional 2 years of HYQVIA treatment and observation, and complete study completion visits at next possible occasion following 36-month visit.
Alternative treatment intervals, such as infusion every 2 weeks, may be considered for tolerability reasons, at discretion of investigator after informing sponsor
arm group label: Epoch 3
arm group type: Active Comparator
description: Approximately one year safety follow-up, if needed: for participants whose anti-rHuPH20 antibody titer was ≥ 160 during Epoch 1 or Epoch 2 and who experience either a study drug related serious adverse event (SAE) or a related severe adverse event (AE) will be followed accordingly.
intervention type: Biological
intervention name: HYQVIA
description: Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with rHuPH20)
arm group label: Epoch 1
arm group label: Epoch 2
other name: IGI 10% with rHuPH20
intervention type: Biological
intervention name: GAMMAGARD LIQUID
description: GAMMAGARD LIQUID IGI (Human), 10% Solution
arm group label: Epoch 3
other name: IGI
other name: 10%
criteria: 
gender: All
minimum age: 2 Years
maximum age: 15 Years
healthy volunteers: No
last name: Study Director
role: Study Director
affiliation: Shire
facility: 
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country: United States
responsible party type: Sponsor
mesh term: Primary Immunodeficiency Diseases
mesh term: Immunologic Deficiency Syndromes
mesh term: Immunoglobulins, Intravenous
sharing ipd: Yes
ipd description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment 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 on https://vivli.org/ourmember/takeda/. 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://vivli.org/ourmember/takeda/
submitted: July 12, 2023
returned: August 2, 2023