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Efficacy, Safety, Tolerability, Immunogenicity and Pharmacokinetic Evaluation of HYQVIA in Pediatric PIDD Subjects

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ClinicalTrials.gov Identifier: NCT03277313
Recruitment Status : Recruiting
First Posted : September 11, 2017
Last Update Posted : December 7, 2018
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Primary Immunodeficiency Diseases (PID) Biological: HYQVIA Biological: GAMMAGARD LIQUID Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Efficacy, Safety, Tolerability, Immunogenicity and Pharmacokinetic Evaluation of HYQVIA in Pediatric Subjects With Primary Immunodeficiency Diseases
Actual Study Start Date : October 17, 2017
Estimated Primary Completion Date : May 30, 2023
Estimated Study Completion Date : May 30, 2023


Arm Intervention/treatment
Experimental: Epoch 1
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.
Biological: HYQVIA
Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with rHuPH20)
Other Name: IGI 10% with rHuPH20

Experimental: 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, at the discretion of investigator and participant.

After one year in Epoch 2, the anti-rHuPH20 binding antibody assay results during that year will be used to decide the next steps in the study:

  • Participants with anti-rHuPH20 antibody titer < 160 at all time-points during the study will complete the study completion visit at the next possible occasion following the 12-months visit.
  • Participants with anti-rHuPH20 antibody titer ≥ 160 during the study and/or at the last measurement will continue in Epoch 2 for an additional two years of HYQVIA treatment and observation, and complete the study completion visits at the next possible occasion following the 36-months visit.
Biological: HYQVIA
Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with rHuPH20)
Other Name: IGI 10% with rHuPH20

Active Comparator: Epoch 3
Safety follow-up for participants whose anti-rHuPH20 antibody titer was ≥ 160 during Epoch 1 or Epoch 2 and who experience either related serious adverse event (SAE) or a related severe adverse event (AE)
Biological: GAMMAGARD LIQUID
GAMMAGARD LIQUID IGI (Human), 10% Solution
Other Names:
  • IGI
  • 10%




Primary Outcome Measures :
  1. Rate of acute serious bacterial infections [ Time Frame: Throughout the study period of approximately five years ]
    The rate of acute serious bacterial infections defined as the mean number of acute serious bacterial infections per participant per year.


Secondary Outcome Measures :
  1. Number of all infections [ Time Frame: Throughout the study period of approximately five years ]
    Number of all infections per patient-year

  2. 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 ]
    Trough levels of immunoglobulin G (IgG) and IgG subclasses for Study Epoch 2

  3. Trough levels of specific antibodies to clinically relevant pathogens [ Time Frame: Epoch 2, Year 1: Month 6. Study Epoch 2, Year 2: Months 24, and 36 ]
    Clinically relevant pathogens include: Clostridium tetani toxoid, Haemophilus influenzae, and Hepatitis B virus [HBV]) for Study Epoch 2

  4. Pharmacokinetics (PK) assessment: Area under the curve (AUC) [ Time Frame: Pre-infusion, within one hour of infusion start time. Post-infusion Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval) ]
    To facilitate comparisons across different dosing intervals (three and four weeks), immunoglobulin G (IgG) exposure (AUC) will be normalized by week.

  5. Pharmacokinetics (PK) assessment: Clearance (CL) [ Time Frame: Pre-infusion, within one hour of infusion start time. Post-infusion Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval) ]
    PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.

  6. Pharmacokinetics (PK) assessment: maximum concentration (Cmax) [ Time Frame: Pre-infusion, within one hour of infusion start time. Post-infusion Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval) ]
    PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.

  7. Pharmacokinetics (PK) assessment: minimum concentration (Cmin) [ Time Frame: Pre-infusion, within one hour of infusion start time. Post-infusion Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval) ]
    PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.

  8. Pharmacokinetics (PK) assessment: time to maximum concentration (Tmax) [ Time Frame: Pre-infusion, within one hour of infusion start time. Post-infusion Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval) ]
    PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.

  9. Pharmacokinetics (PK) assessment: terminal half-life (T 1/2) [ Time Frame: Pre-infusion, within one hour of infusion start time. Post-infusion Days 4, 10, and either day 21 (for 3 week treatment interval), or day 28 (for 4 week treatment interval) ]
    PK analyses will use the actual observed sample drawing times, not the nominal times specified in the protocol.

  10. Number of serious adverse events (SAEs), related and not related [ Time Frame: Throughout the study period of approximately five years ]
    Number of serious adverse events (SAEs) per infusion (excluding infections), related and not related

  11. Rate of serious adverse events (SAEs), related and not related [ Time Frame: Throughout the study period of approximately five years ]
    Rate of serious adverse events (SAEs) per infusion (excluding infections), related and not related

  12. Number of all adverse events (AEs), related and not related [ Time Frame: Throughout the study period of approximately five years ]
    Number of all adverse events (AEs) per infusion (excluding infections), related and not related

  13. Rate of all adverse events (AEs), related and not related [ Time Frame: Throughout the study period of approximately five years ]
    Rate of all adverse events (AEs) per infusion (excluding infections), related and not related

  14. Number of local adverse events (AEs), related and not related [ Time Frame: Throughout the study period of approximately five years ]
    Number of local adverse events (AEs) per infusion (excluding infections), related and not related

  15. Rate of local adverse events (AEs), related and not related [ Time Frame: Throughout the study period of approximately five years ]
    Rate of local adverse events (AEs) per infusion (excluding infections), related and not related

  16. Number of systemic adverse events (AEs), related and not related [ Time Frame: Throughout the study period of approximately five years ]
    Number of systemic adverse events (AEs) per infusion (excluding infections), related and not related

  17. Rate of systemic adverse events (AEs), related and not related [ Time Frame: Throughout the study period of approximately five years ]
    Rate of systemic adverse events (AEs) per infusion (excluding infections), related and not related

  18. 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. ]
    Temporally associated AEs are all AEs which begin during the infusion or within 72 hours of completion of infusion.

  19. 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. ]
    Temporally associated AEs are all AEs which begin during the infusion or within 72 hours of completion of infusion.

  20. Number of all causally related and/or temporally associated adverse events (AEs) per infusion (excluding infections) [ Time Frame: Throughout the study period of approximately five years ]
    Number per infusion (excluding infections) of all causally related and/or temporally associated AEs

  21. Rate of all causally related and/or temporally associated adverse events (AEs) per infusion (excluding infections) [ Time Frame: Throughout the study period of approximately five years ]
    Rate per infusion (excluding infections) of all causally related and/or temporally associated AEs

  22. Rates of all AEs (excluding infections) [ Time Frame: Throughout the study period of approximately five years ]
    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

  23. 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) ]
    Number of participants who develop positive titer (≥ 160) of binding or neutralizing antibodies to rHuPH20

  24. 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) ]
    Percentage of participants who develop positive titer (≥ 160) of binding or neutralizing antibodies to rHuPH20

  25. Number of infusions per month [ Time Frame: Epoch 2 (up to 3 years) ]
    Median number of infusions per month per participant

  26. Number of infusion sites (needle sticks) per infusion/month [ Time Frame: Epoch 2 (up to 3 years) ]
    Median number of infusion sites (needle sticks) per infusion/month

  27. Duration of infusion [ Time Frame: Epoch 2 (up to 3 years) ]
    Median duration of infusion

  28. Maximum infusion rate / site [ Time Frame: Epoch 2 (up to 3 years) ]
    Median maximum infusion rate / site

  29. Infusion volume / site [ Time Frame: Epoch 2 (up to 3 years) ]
    Median infusion volume / site

  30. Infusions that are discontinued, slowed, or interrupted due to an adverse event (AE) [ Time Frame: Epoch 2 (up to 3 years) ]
    Number of infusions that are discontinued, slowed, or interrupted due to an adverse event (AE)

  31. 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) ]
    Percentage of infusions that are discontinued, slowed, or interrupted due to an AE

  32. Number of weeks to reach final dose interval [ Time Frame: Epoch 1 (up to 6 weeks) ]
    Median number of weeks to reach final dose interval (three weeks or four weeks) (Epoch 1)

  33. 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) ]
    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

  34. Percentage of participants who maintain a treatment interval of three or four weeks in Epoch 2 for 12 months [ Time Frame: 12 months ]
    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

  35. 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 ]
    The Peds-QL is a generic Health-Related Quality of Life (HRQoL) instrument designed specifically for a pediatric population.

  36. 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 ]
    EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-case, usual activities, pain/discomfort and anxiety/depression.

  37. Treatment Preference and Satisfaction: Assessment of Life Quality Index (LQI) [ Time Frame: Epoch 1: Baseline (First Infusion); Epoch 2: months 12, 24, and 36 ]
    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.

  38. 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 ]
    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.

  39. Treatment Preference and Satisfaction: Assessment of Treatment Preference Questionnaire [ Time Frame: Epoch 2: months 12, 24, and 36 ]
    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.

  40. 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 five years ]
    Days not able to go to school or work, or to perform normal daily activities due to infection or other illnesses per patient-year

  41. Health Resource Utilization: Days on antibiotics [ Time Frame: Throughout the study period of approximately five years ]
    Days on antibiotics per patient-year

  42. Health Resource Utilization: Number of hospitalizations [ Time Frame: Throughout the study period of approximately five years ]
    Number of hospitalizations, indication for the hospitalization (infection or non-infection)

  43. Health Resource Utilization: Number of days hospitalized [ Time Frame: Throughout the study period of approximately five years ]
    Number of days hospitalized per patient-year

  44. Health Resource Utilization: Number of acute physician visits [ Time Frame: Throughout the study period of approximately five years ]
    Number of acute physician visits (office and emergency room) due to infection or other illnesses per patient-year



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant must have a documented diagnosis of a form of primary immunodeficiency (PI) involving a defect in antibody formation and requiring gammaglobulin replacement, as defined according to the International Union of Immunological Societies (IUIS) Scientific Committee 2015 1 prior to enrollment. The diagnosis must be confirmed by the sponsor´s Medical Director prior to first treatment with IP in the study.
  2. Participant is at least two and below 16 years of age at the time of screening.
  3. Participant has been receiving a consistent dose of Immunoglobulin G (IgG), administered in compliance with the respective product information for a period of at least three months prior to screening. The average minimum pre-study dose over that interval was equivalent to 300 mg/kg BW / 4 weeks and a maximum dose equivalent to 1000 mg/kg body weight (BW) / 4 weeks.
  4. Participant has a serum trough level of IgG > 5 g/L at screening.
  5. If female of childbearing potential, participant presents with a negative pregnancy test and agrees to employ adequate birth control measures for the duration of the study.
  6. Participant /legally authorized representative is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

  1. Participant has a known history of or is positive at screening for one or more of the following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1/2.
  2. Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent):

    1. Persistent alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 times the upper limit of normal (ULN) for the testing laboratory
    2. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] ≤ 500/mm^3)
  3. Participant has anemia that would preclude phlebotomy for laboratory studies, according to standard practice at the site.
  4. Participant has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following intravenous (IV) immunoglobulin, subcutaneous (SC) immunoglobulin, and/or Immune Serum Globulin (ISG) infusions.
  5. Participant has severe Immunoglobulin A (IgA) deficiency (less than 7.0 mg/dL) with known anti-IgA antibodies and a history of hypersensitivity.
  6. Participant has a known allergy to hyaluronidase.
  7. Participant has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening.
  8. Participant has a bleeding disorder or a platelet count less than 20,000/μL, or who, in the opinion of the investigator, would be at significant risk of increased bleeding or bruising as a result of SC therapy.
  9. Participant has severe dermatitis that would preclude adequate sites for safe product administration in the opinion of the investigator.
  10. Participant has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
  11. Participant is a family member or employee of the investigator.
  12. If female, participant is pregnant or lactating at the time of enrollment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03277313


Contacts
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Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com

Locations
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United States, Alabama
University of Alabama Medical Center Recruiting
Birmingham, Alabama, United States, 35294
Contact: Site Contact    205-934-8347    patkinso@uab.edu   
Principal Investigator: Prescott Atkinson         
United States, Connecticut
Connecticut Children's Medical Center Recruiting
Hartford, Connecticut, United States, 06106
Contact: Site Contact    860-837-5873    nbennett01@connecticutchildrens.org   
Principal Investigator: Nicholas Bennett         
United States, Florida
University of Miami Pediatric Allergy and Immunology Recruiting
Miami, Florida, United States, 33136
Contact: Site Contact    305-243-4304    gary.kleiner@med.miami.edu   
Principal Investigator: Gary Kleiner         
University of South Florida Physician Group Recruiting
Saint Petersburg, Florida, United States, 33701
Contact: Site Contact    727-553-1259    jolanwalter@health.usf.edu   
Principal Investigator: Jolan Walter         
United States, Georgia
Georgia Pollens Clinical Research Centers, Inc. Recruiting
Albany, Georgia, United States, 31707
Contact: Site Contact    229-883-8909    tbrid70463@aol.com   
Principal Investigator: Tracy Bridges         
Emory Healthcare Recruiting
Atlanta, Georgia, United States, 30322
Contact: Site Contact    404-727-5642    lkobryn@emory.edu   
Principal Investigator: Lisa Kobrynski         
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Site Contact    617-919-6041    rima.rachid@childrens.harvard.edu   
Principal Investigator: Rima Rachid         
United States, Missouri
Washington University Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Contact    314-747-1217    cooper_m@wustl.edu   
Principal Investigator: Megan Cooper         
United States, New York
Women & Children's Hospital of Buffalo Recruiting
Buffalo, New York, United States, 14203
Contact: Site Contact    716-209-7200 ext 323    hkm@buffalo.edu   
Principal Investigator: Heather Lehman         
Northwell Health, Inc. PRIME Recruiting
Great Neck, New York, United States, 11021
Contact: Site Contact    516-622-5070    vbonagura@northwell.edu   
Principal Investigator: Vincent Bonagura         
Stony Brook Children's Hospital Recruiting
Stony Brook, New York, United States, 11794
Contact: Site Contact    631-444-8832    susan.schuval@stonybrookmedicine.edu   
Principal Investigator: Susan Schuval         
United States, North Carolina
Carolinas Healthcare System Recruiting
Charlotte, North Carolina, United States, 28203
Contact: Site Contact    704-506-3748    niraj.patel@atriumhealth.org   
Principal Investigator: Niraj Patel         
Allergy Asthma & Immunology Relief of Charlotte Recruiting
Charlotte, North Carolina, United States, 28277
Contact: Site Contact    704-910-1402 ext 350    droconnor@aairofcharlotte.com   
Principal Investigator: Maeve O'Connor         
United States, Oklahoma
OK Institute of Allergy & Asthma Clinical Research, LLC Recruiting
Oklahoma City, Oklahoma, United States, 73131
Contact: Site Contact    405-607-4333 ext 126    research@okallergy.com   
Principal Investigator: Amy Darter         
Vital Prospects Clinical Research Institute, P.C. Recruiting
Tulsa, Oklahoma, United States, 74136
Contact: Site Contact    918-392-4550 ext 214    iftikhar.hussain@aaicenter.net   
Principal Investigator: Iftikar Hussain         
United States, Texas
Allergy Partners of North Texas Research Recruiting
Dallas, Texas, United States, 75230
Contact: Site Contact    972-566-6801    drrichwasserman@gmail.com   
Principal Investigator: Richard Wasserman         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Site Contact    801-585-5067    karin.chen@hsc.utah.edu   
Principal Investigator: Karin Chen         
United States, Virginia
Section on Immunopathogenesis and Clinical Immunology Recruiting
Fairfax, Virginia, United States, 22030
Contact: Site Contact    240-643-6002    oalpan@me.com   
Principal Investigator: Oral Alpen         
United States, West Virginia
Marshall University Joan C. Edwards School of Medicine Recruiting
Charleston, West Virginia, United States, 25701
Contact: Site Contact    304-691-6859    watts50@marshall.edu   
Principal Investigator: Meagan Shepherd         
Sponsors and Collaborators
Baxalta now part of Shire
Baxalta Innovations GmbH, now part of Shire
Investigators
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Study Director: Study Director Shire

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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT03277313     History of Changes
Other Study ID Numbers: 161503
First Posted: September 11, 2017    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Immunologic Deficiency Syndromes
Immune System Diseases
Immunoglobulins, Intravenous
gamma-Globulins
Rho(D) Immune Globulin
Immunologic Factors
Physiological Effects of Drugs