Post-Authorization Safety, Tolerability and Immunogenicity Evaluation of HyQvia in Pediatric PIDD Subjects

Study Overview
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Brief Summary
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The purpose of the study is to acquire additional data on safety, tolerability and immunogenicity of HyQvia in pediatric (age two to <18 years) patients with Primary Immunodeficiency Diseases (PIDD)

Official Title
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Post-Authorization Safety, Tolerability and Immunogenicity Evaluation of HyQvia in Pediatric Subjects With Primary Immunodeficiency Diseases

Conditions
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Primary Immunodeficiency Diseases (PID)

Intervention / Treatment
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* Biological: HYQVIA
* Biological: KIOVIG
* Biological: Cuvitru


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have a documented diagnosis of a form of primary humoral immunodeficiency involving a defect in antibody formation and requiring gammaglobulin replacement, as defined according to the International Union of Immunological Societies (IUIS) Scientific Committee 2015 prior to enrollment. The diagnosis must be confirmed by the sponsor´s Medical Director prior to first treatment with investigational product (IP) in the study. Participant is at least two and below 18 years of age at the time of screening. 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 body weight (BW)/four weeks and a maximum dose equivalent to 1000 mg/kg BW/4 weeks. Participant has a serum trough level of IgG > 5 g/L at screening. 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. Participant /legally authorized representative is willing and able to comply with the requirements of the protocol. Exclusion Criteria: 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. Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent): Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) >2.5 times the upper limit of normal (ULN) for the testing laboratory Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] ≤ 500/mm^3) Participant has anemia that would preclude phlebotomy for laboratory studies, according to standard practice at the site. 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. Participant has severe immunoglobulin A (IgA) deficiency (< 7.0 mg/dL) with known anti-IgA antibodies and a history of hypersensitivity. . Participant has a known allergy to hyaluronidase. Participant has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening. Participant has a bleeding disorder or a platelet count < 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. Participant has severe dermatitis that would preclude adequate sites for safe product administration in the opinion of the investigator. 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. Participant is a family member or employee of the investigator. If female, participant is pregnant or lactating at the time of enrollment.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPOCH 1<br>Ramp up period for participants who were not treated with HyQvia prior to this study | Biological: HYQVIA<br>* Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with rHuPH20)<br>* Other names: IGI 10% with rHuPH20;|
| Experimental: EPOCH 2<br>Participants who were treated with HyQvia prior to this study, and those who completed the ramp up period (Epoch 1). After one year in Epoch 2, participants with anti-rHuPH20 antibody titer <160 at all time-points during the study will complete the study termination/completion visit at the next possible occasion. Participants with anti-rHuPH20 antibody titer >=160 during the study and/or at the last measurement will continue for an additional two years of HyQvia treatment and observation. | Biological: HYQVIA<br>* Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with rHuPH20)<br>* Other names: IGI 10% with rHuPH20;|
| Experimental: Epoch 3<br>Safety follow-up for participants whose anti-rHuPH20 antibody titer was >= 160 during Epoch 1 or Epoch 2 and who experience either a related serious adverse event (SAE) or a related severe adverse event (AE) | Biological: KIOVIG<br>* 100 mg/ml solution for Immune Globulin Intravenous Infusion<br>* Other names: IGI 10%;Biological: Cuvitru<br>* 200 mg/ml solution for Immune Globulin Subcutaneous Injection<br>* Other names: IGI 20%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of Participants With Any Severe Related Treatment-emergent Adverse Events (TEAEs) Per Infusion (Excluding Infections) | An Adverse Event (AE) was defined as any untoward medical occurrence in a participant administered an investigational product (IP) that does not necessarily have a causal relationship with the treatment. TEAEs were the AEs with onset after date-time of first dose of IP, or any medical condition present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. TEAEs that were recorded as possibly related or probably related to HYQVIA were considered HYQVIA-related adverse events. Number of participants with any severe related TEAEs (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of Any Severe Related TEAEs Per Infusion (Excluding Infections) | An AE was defined as any untoward medical occurrence in a participant administered an IP that does not necessarily have a causal relationship with the treatment. TEAEs were the AEs with onset after date-time of first dose of IP, or any medical condition present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. TEAEs that were recorded as possibly related or probably related to HYQVIA were considered HYQVIA-related adverse events. Severe related TEAEs rate per infusion was calculated as number of severe related TEAEs/total number of infusions administered to participants in the analysis set. Rate of any severe related TEAEs per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Any Related Serious TEAEs Per Infusion (Excluding Infections) | TEAEs were the AEs with onset after date-time of first dose of IP, or any medical condition present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs that were recorded as possibly related or probably related to HYQVIA were considered HYQVIA-related adverse events. Number of participants with any related serious TEAEs per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of Any Related Serious TEAEs Per Infusion (Excluding Infections) | TEAEs were the AEs with onset after date-time of first dose of IP, or any medical condition present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in-patient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs that were recorded as possibly related or probably related to HYQVIA were considered HYQVIA-related adverse events. Rate of related serious TEAEs per infusion was calculated as number of related serious TEAEs/total number of infusions administered to participants in the analysis set. Rate of any related serious TEAEs per Infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Change From Baseline in Total Serum Trough Levels of Immunoglobulin G (IgG) at Month 12 | Change from baseline in total serum trough levels of IgG in Epoch 1 and 2 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. | Baseline, Month 12 | 
| Efficacy: Change From Baseline in Serum Trough Levels of IgG Subclasses at Month 12 | Change from baseline in Serum trough levels of IgG subclasses 1, 2, 3, and 4 in Epoch 1 and 2 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. | Baseline, Month 12 | 
| Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Clostridium Tetani Toxoid IgG at Month 12 | Change from baseline in trough levels of specific antibodies in clostridium tetani toxoid IgG at Month 12 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. Here, IU/ml was defined as International units per milliliter. | Baseline, Month 12 | 
| Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Hepatitis B Virus (HBV) at Month 12 | Change from baseline in trough levels of specific antibodies in HBV at Month 12 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. | Baseline, Month 12 | 
| Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Haemophilus Influenzae B IgG at Month 12 | Change from baseline in trough levels of specific antibodies in Haemophilus influenzae B IgG at Month 12 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. | Baseline, Month 12 | 
| Safety: Percentage of Participants Who Achieved a Treatment Interval of Three or Four Weeks in Epoch 2 | Percentage of participants who achieved a treatment interval of three or four weeks in Epoch 2 was reported. | Up to 20 months | 
| Safety: Percentage of Participants Who Maintained a Treatment Interval of Three or Four Weeks in Epoch 2 up to 12 Months | Percentage of participants who maintained a treatment interval of three or four weeks in Epoch 2 up to 12 months was reported. | Up to 12 months | 
| Safety: Number of Participants With Local TEAEs (Excluding Infections) | TEAEs were the AEs with onset after date-time of first dose of IP, or any medical condition present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Number of Participants with local TEAEs (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of Local TEAEs Per Infusion (Excluding Infections) | Rate of local TEAEs per infusion was calculated as number of local adverse events/total number of infusions administered to participants in the analysis set. Only events are included which start prior to participants start date of non-response. Rate of local TEAEs per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Local Adverse Reaction (Excluding Infections) | Adverse reaction was defined as any TEAE that meets any of the following criteria: 1) A TEAE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or; 2) A TEAE that begins during infusion of IP or within 72 hours following the end of IP infusion, or; 3) A TEAE for which causality assessment is missing or indeterminate. Number of participants with local adverse reactions (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of Local Adverse Reaction Per Infusion (Excluding Infections) | Rate of local adverse reaction per infusion was calculated as number of local adverse reaction events/total number of infusions administered to participants in the analysis set. Rate of local adverse reactions per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Systemic TEAEs (Excluding Infections) | TEAEs were the AEs with onset after date-time of first dose of IP, or any medical condition present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Number of participants with systemic TEAEs (excluding infections) was reported.. | From start of study drug administration up to 20 months | 
| Safety: Rate of Systemic TEAEs Per Infusion (Excluding Infections) | Rate of systemic TEAEs per infusion was calculated as number of systemic adverse events/total number of infusions administered to participants in the analysis set. Rate of systemic TEAEs per infusion was assessed based on events per infusion. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Systemic Adverse Reaction (Excluding Infections) | Adverse reaction was defined as any TEAE that meets any of the following criteria: 1) A TEAE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or; 2) A TEAE that begins during infusion of IP or within 72 hours following the end of IP infusion, or; 3) A TEAE for which causality assessment is missing or indeterminate. Number of participants with systemic adverse reaction (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of Systemic Adverse Reaction Per Infusion (Excluding Infections) | Rate of Systemic adverse reactions per infusion was calculated as number of systemic adverse reaction events/total number of infusions administered to participants in the analysis set. Rate of systemic adverse reactions per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Any TEAEs (Excluding Infections) | TEAEs were the AEs with onset after date-time of first dose of IP, or any medical condition present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Number of participants with any TEAEs (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of TEAEs Per Infusion (Excluding Infections) | Rate of TEAEs per infusion was calculated as number of adverse events/total number of infusions administered to participants in the analysis set. Rate of TEAEs per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Any Adverse Reactions (Excluding Infections) | Adverse reaction was defined as any TEAE that meets any of the following criteria: 1) A TEAE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or; 2) A TEAE that begins during infusion of IP or within 72 hours following the end of IP infusion, or; 3) A TEAE for which causality assessment is missing or indeterminate. Number of participants with any adverse reactions (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of Any Adverse Reaction Per Infusion (Excluding Infections) | Rate of all adverse reactions per infusion was calculated as number of adverse reaction events/total number of infusions administered to participants in the analysis set. Rate of any adverse reactions per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Any Temporally Associated TEAEs (Excluding Infections) | Temporally-associated TEAEs were defined as TEAEs which begin during infusion of IP or within 72 hours following the end of IP infusion. Number of participants with any temporally associated TEAEs (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of Any Temporally Associated TEAEs Per Infusion (Excluding Infections) | Rate of any temporally associated TEAEs per infusion was calculated as number of temporally associated adverse events/total number of infusions administered to participants in the analysis set. Temporally-associated TEAEs were defined as TEAEs which begin during infusion of IP or within 72 hours following the end of IP infusion. Rate of any temporally associated TEAEs per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Any Related (Causally) and/or Temporally Associated TEAEs (Excluding Infections) | Number of participants with any related (causally) and/or temporally associated TEAEs (excluding infections) was reported. Temporally-associated TEAEs were defined as TEAEs which begin during infusion of IP or within 72 hours following the end of IP infusion. | From start of study drug administration up to 20 months | 
| Safety: Rate of Any Related (Causally) and/or Temporally Associated TEAEs Per Infusion (Excluding Infections) | Rate of any related (causally) and/or temporally associated TEAEs per infusion was calculated as number of related and/or temporally associated adverse events/ total number of infusions administered to participants in the analysis set. TEAEs recorded in the study database as possibly related or probably related to HYQVIA are considered HYQVIA-related adverse events. Temporally-associated TEAEs were defined as TEAEs which begin during infusion of IP or within 72 hours following the end of IP infusion. Rate of any related (causally) and/or temporally associated TEAEs per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants With Any Serious TEAEs (Excluding Infections) | Serious TEAE were the AEs that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in-patient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Number of participants with any serious TEAEs (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Rate of Serious TEAEs Per Infusion (Excluding Infections) | Rate of serious TEAEs per infusion was calculated as number of serious adverse events/total number of infusions administered to participants in the analysis set. Rate of serious TEAEs per infusion (excluding infections) was reported. | From start of study drug administration up to 20 months | 
| Safety: Number of Participants Who Developed Positive Titer (>=160) of Binding or Neutralizing Antibodies to rHuPH20 | Number of participants who developed positive titer (>=160) of binding or neutralizing antibodies to rHuPH20 was reported. | From start of study drug administration up to 20 months | 
| Other Analysis: Number of Infusions Per Month | Number of infusions per month was calculated as total number of infusions per duration of treatment (days) * 30.4 days per month. | Up to 20 months | 
| Other Analysis: Number of Infusion Sites (Needle-Sticks) Per Infusion | Number of infusion sites (needle-sticks) per infusion was calculated as total number of infusion sites / total number of infusions. Only infusions with complete data available were included. | Up to 20 months | 
| Other Analysis: Number of Infusion Sites (Needle-Sticks) Per Month | Number of infusion sites per month was calculated as total number of infusion sites / duration of treatment (days) * 30.4 days. Only infusions with complete data available were included. | Up to 20 months | 
| Other Analysis: Duration of Infusion | The duration of infusion was defined as the difference between the end time and the start time of the HyQvia infusion. | From start of study drug administration up to 20 months. | 
| Other Analysis: Maximum Infusion Rate Per Site | Maximum infusion rate per site was reported. | Up to 20 months | 
| Other Analysis: Infusion Volume Per Site | Infusion volume per site was calculated as actual IgG volume (milliliter [mL]) / total number of infusion sites (hour) used. | Up to 20 months | 
| Other Analysis: Number of Infusions That Were Interrupted or Stopped Due to an AE | Number of infusions that were interrupted or Stopped due to an AE was reported. | Up to 20 months | 
| Other Analysis: Number of Weeks to Reach Final 3 or 4-week Dose Interval in Epoch 1 | Final dose interval, defined as three or four weeks infusion interval in Epoch 1 of treatment period, was reported. | Up to 20 months | 
| Health Related Quality of Life (HR QoL): Change From Baseline in Pediatric Quality of Life Questionnaire (PedsQL) | PedsQL Generic Core Scale (GCS) was used for QOL assessment. It encompasses 4 dimensions (physical functioning [PF], emotional functioning [EF], social functioning [SF], school functioning [ScF]). Age groups are: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years), and Teens (13-<18 years). Depending on the participants age, the questionnaire may be completed by either the participant or the parent/caregiver as appropriate. For the Toddler group, the PedsQL GCS consisted of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL consisted of 23 items, with a 3-point Likert scale (0, 2, 4) for the young child, and a 5-point Likert scale for the child and teens groups. All Scores were transformed on a scale from 0 to 100 where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores indicate better quality of life. A negative change from baseline indicates worse quality of life. Baseline: last non-missing value before the initial dose of HYQVIA. | Baseline up to 20 months | 
| HRQoL: Change From Baseline in EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) | EQ-5D considered five attributes of quality of life evaluation, that is, mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each dimension had five possible levels: 1 (no problems); 2 (slight problems); 3 (moderate problems); 4 (severe problems), and; 5 (extreme problems). The participants rating of their current HRQoL state was recorded using a standard vertical 20-cm visual analog scale (EQ-VAS), which ranged from 0 to 100, where 0 indicated worst imaginable health state and 100 was best imaginable health state. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. A negative change from baseline indicates worse health state. | Baseline up to 20 months | 
| HR QoL: Change From Baseline in Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) | TSQM-9 is a 9-item, validated, self-administered instrument to assess participants satisfaction with medication. It consists of 3 subscales: effectiveness, convenience and global satisfaction. The scores were computed by adding items for each domain, i.e. 1 to 3 for effectiveness, 4 - 6 for convenience and 7 to 9 for global satisfaction. The lowest possible score (1 for each item and 3 for all 3 subscales) was subtracted from the composite score and divided by the greatest possible score range. The greatest range was (7-1)*3 items = 18 for the effectiveness and convenience, and (5-1)*3 items = 12 for global satisfaction . The item scores of each of the 3 domains are summed and transformed to create a score of 0 (extremely dissatisfied) to 100 (extremely satisfied). Higher score indicated greater satisfaction in that domain. A negative change from baseline indicates less satisfaction in that domain. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. | Baseline up to 20 months |