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

Phase 4

Completed

Conditions: Primary Immunodeficiency Diseases (PID)

Interventions: Biological: HYQVIA
Biological: KIOVIG
Biological: Cuvitru

Registration Number: NCT03116347

Lead Sponsor: Baxalta now part of Shire

Brief Summary: 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)

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 42

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):
1. Persistent alanine aminotransferase (ALT) and aspartate amino transferase (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)
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
EPOCH 1	HYQVIA	Ramp up period for participants who were not treated with HyQvia prior to this study
Epoch 3	KIOVIG	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)
EPOCH 2	HYQVIA	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.
Epoch 3	Cuvitru	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)

Primary Outcome Measures

Name	Time	Method
Safety: Number of Participants With Any Severe Related Treatment-emergent Adverse Events (TEAEs) Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Any Severe Related TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants With Any Related Serious TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Any Related Serious TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.

Secondary Outcome Measures

Name	Time	Method
Efficacy: Change From Baseline in Total Serum Trough Levels of Immunoglobulin G (IgG) at Month 12	Baseline, 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.
Efficacy: Change From Baseline in Serum Trough Levels of IgG Subclasses at Month 12	Baseline, 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.
Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Clostridium Tetani Toxoid IgG at Month 12	Baseline, 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".
Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Hepatitis B Virus (HBV) at Month 12	Baseline, 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.
Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Haemophilus Influenzae B IgG at Month 12	Baseline, 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.
Safety: Percentage of Participants Who Achieved a Treatment Interval of Three or Four Weeks in Epoch 2	Up to 20 months	Percentage of participants who achieved a treatment interval of three or four weeks in Epoch 2 was reported.
Safety: Number of Participants With Any TEAEs (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Percentage of Participants Who Maintained a Treatment Interval of Three or Four Weeks in Epoch 2 up to 12 Months	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.
Safety: Number of Participants With Local TEAEs (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Local TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants With Local Adverse Reaction (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Local Adverse Reaction Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants With Systemic TEAEs (Excluding Infections)	From start of study drug administration up to 20 months	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..
Safety: Rate of Systemic TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants With Systemic Adverse Reaction (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Systemic Adverse Reaction Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants With Any Adverse Reactions (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Any Adverse Reaction Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants With Any Temporally Associated TEAEs (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Any Temporally Associated TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants With Any Related (Causally) and/or Temporally Associated TEAEs (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Any Related (Causally) and/or Temporally Associated TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants With Any Serious TEAEs (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Rate of Serious TEAEs Per Infusion (Excluding Infections)	From start of study drug administration up to 20 months	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.
Safety: Number of Participants Who Developed Positive Titer (>=160) of Binding or Neutralizing Antibodies to rHuPH20	From start of study drug administration up to 20 months	Number of participants who developed positive titer (\>=160) of binding or neutralizing antibodies to rHuPH20 was reported.
Other Analysis: Number of Infusions Per Month	Up to 20 months	Number of infusions per month was calculated as total number of infusions per duration of treatment (days) \* 30.4 days per month.
Other Analysis: Number of Infusion Sites (Needle-Sticks) Per Infusion	Up to 20 months	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.
Other Analysis: Number of Infusion Sites (Needle-Sticks) Per Month	Up to 20 months	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.
Other Analysis: Duration of Infusion	From start of study drug administration up to 20 months.	The duration of infusion was defined as the difference between the end time and the start time of the HyQvia infusion.
Other Analysis: Maximum Infusion Rate Per Site	Up to 20 months	Maximum infusion rate per site was reported.
Other Analysis: Infusion Volume Per Site	Up to 20 months	Infusion volume per site was calculated as actual IgG volume (milliliter \[mL\]) / total number of infusion sites (hour) used.
Other Analysis: Number of Infusions That Were Interrupted or Stopped Due to an AE	Up to 20 months	Number of infusions that were interrupted or Stopped due to an AE was reported.
Other Analysis: Number of Weeks to Reach Final 3 or 4-week Dose Interval in Epoch 1	Up to 20 months	Final dose interval, defined as three or four weeks infusion interval in Epoch 1 of treatment period, was reported.
Health Related Quality of Life (HR QoL): Change From Baseline in Pediatric Quality of Life Questionnaire (PedsQL)	Baseline up to 20 months	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.
HRQoL: Change From Baseline in EuroQoL (Quality of Life)-5 Dimensions (EQ-5D)	Baseline up to 20 months	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.
HR QoL: Change From Baseline in Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9)	Baseline up to 20 months	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.

Trial Locations

Locations (20): General Hospital of Thessaloniki Papageorgiou
🇬🇷
Thessaloniki, Greece
1.Detská klinika
🇸🇰
Bratislava, Slovakia
Univerzitna Nemocnica Klinika detí a dorastu
🇸🇰
Martin, Slovakia
FN v Motole Interni klinika
🇨🇿
Prague, Czechia
Fakultni nemocnice Brno Odd. Detska klinika
🇨🇿
Brno, Czechia
General Hospital of Thessaloniki Ippokrateio
🇬🇷
Thessaloniki, Greece
Groupe Hospitalier Pellegrin - Hôpital des Enfants
🇫🇷
Bordeaux, Gironde, France
CHU Angers - Hôpital Hôtel Dieu
🇫🇷
Angers, France
The Great North Children's Hospital Royal Victoria Infirmary
🇬🇧
Newcastle upon Tyne, United Kingdom
Royal Victoria Hospital
🇬🇧
Belfast, United Kingdom
Dept. of Pediatric Oncology/Hematology/Immunology-Skånes Universitetssjukhus
🇸🇪
Lund, Sweden
Leeds Children's Hospital
🇬🇧
Leeds, West Yorkshire, United Kingdom
United St. Istvan and St. Laszlo Hospital
🇭🇺
Budapest, Hungary
Rigshospitalet
🇩🇰
København, Denmark
Queen Silvia Children's Hospital
🇸🇪
Goteborg, Sweden
Hospices Civils de Lyon - Hôpitaux Est - IHOP
🇫🇷
Lyon, France
University Hospital of Wales Heath Park Clinical Research Facility
🇬🇧
Cardiff, United Kingdom
Agia Sophia Children's Hospital
🇬🇷
Athens, Greece
Bristol Royal Hospital for Children
🇬🇧
Bristol, Avon, United Kingdom
Fakultní nemocnice Hradec Králové
🇨🇿
Nový Hradec Králové, Czechia