Tolerability and Safety of Immune Globulin Subcutaneous Solution (IGSC) and rHuPH20 in PID

Study Overview
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Brief Summary
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The original purpose of the study is to assess the long-term safety, tolerability, and practicability of the subcutaneous (SC) treatment with Immune Globulin Subcutaneous Solution (IGSC), 10% facilitated with recombinant human hyaluronidase (rHuPH20) in participants with Primary Immunodeficiency Diseases (PID) who have completed Baxter Clinical Study Protocol No. 160603. Following a discussion with the FDA, all participants still active in the study stopped treatment with rHuPH20 to assure safety of the participants participating in the study and went into a safety follow-up. During this safety follow-up period, participants underwent either intravenous (IV) or SC treatment with IGSC, 10%. The IV or SC administration route was at the discretion of the participant and the investigator.

Detailed Description
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IGSC, 10% is the same product as IMMUNE GLOBULIN INTRAVENOUS (HUMAN), 10% (IGIV, 10%) quoted in study 160603. IGSC, 10% is abbreviated to IGI, 10% [IMMUNE GLOBULIN INFUSION (HUMAN), 10%] In the US the product is licensed (trade name GAMMAGARD LIQUID) for the intravenous (IV) and SC replacement therapy of antibody deficiency in patients with PID. In the EU this product is licensed (trade name KIOVIG) IGSC, 10% with rHuPH20 established name is Innume Glubulin Infusion 10% (Human) with Recombinant Human Hyualuronidase. US trade name is HYQVIA EU trade name is HyQvia

Official Title
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Long-Term Tolerability and Safety of Immune Globulin Subcutaneous (IGSC) Solution Administered Subcutaneously Following Administration of Recombinant Human Hyaluronidase (rHuPH20) in Subjects With Primary Immunodeficiency Diseases

Conditions
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Primary Immunodeficiency Diseases (PID)

Intervention / Treatment
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* Biological: SC treatment with IGSC, 10% with rHuPH20 followed by SC/IGSC, 10% only (safety)
* Biological: SC treatment with IGSC, 10% with rHuPH20 followed by IV/IGSC, 10% only (safety)
* Biological: IV treatment with IGSC, 10%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has completed or is about to complete Baxter Clinical Study Protocol No. 160603. Participants who have discontinued rHuPH20 and reverted to intravenous or subcutaneous treatment due to an anti-rHuPH20 antibody also may enroll for long-term safety monitoring. Participant/caretaker has reviewed, signed and dated informed consent Participant is willing and able to comply with the requirements of the protocol Exclusion Criteria: Participant has a serious medical condition such that the participant's safety or medical care would be impacted by participation in Study 160902 Participant is scheduled to participate in another non-Baxter clinical study involving an investigational product or investigational device during the course of this study If female of childbearing potential, participant is pregnant or has a negative pregnancy test and does not agree to employ adequate birth control measures for the duration of the study

Ages Eligible for Study
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Minimum Age: 2 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: SC/IGSC, 10% with rHuPH20 followed by SC of IGSC, 10% (safety)<br>Efficacy and safety of subcutaneous (SC) administration of Immune Globulin Subcutaneous Solution (IGSC), 10% after SC administration of recombinant human hyaluronidase (rHuPH20) followed by Safety of SC of IGSC, 10% only (safety follow-up) | Biological: SC treatment with IGSC, 10% with rHuPH20 followed by SC/IGSC, 10% only (safety)<br>* Participants are to continue on the same doses and treatment intervals of IGSC, 10% adjusted for body weight, and rHuPH20 that were used for the last infusions in Study epoch 2 of Study 160603 (NCT00814320). After 3 infusions, participants are to change treatment to a 2-week interval, if agreed with participant and investigator. During this safety follow-up period, participants are treated with IGSC, 10% via the SC route. Treatment occurred once every week. The dose was the weekly equivalent of the most recent IV dose (adjusted per body weight) and multiplied by 1.37.<br>* Other names: 10% [EU]);|
| Experimental: SC/IGSC, 10% with rHuPH20 followed by IV of IGSC, 10% (safety<br>Efficacy and safety of subcutaneous (SC) administration of Immune Globulin Subcutaneous Solution (IGSC), 10% after SC administration of recombinant human hyaluronidase (rHuPH20) followed by Safety of intravenous (IV) administration of IGSC, 10% only (safety follow-up) | Biological: SC treatment with IGSC, 10% with rHuPH20 followed by IV/IGSC, 10% only (safety)<br>* Participants are to continue on the same doses and treatment intervals of IGSC, 10% adjusted for body weight, and rHuPH20 that were used for the last infusions in Study epoch 2 of Study 160603 (NCT00814320). After 3 infusions, participants are to change treatment to a 2-week interval, if agreed with participant and investigator. During this safety follow-up period, participants are treated with IGSC, 10% via the intravenous (IV) route. Treatment occurred once every 3-4 weeks. The weekly dose equivalent was 100% of the most recent IV dose.<br>* Other names: 10% with rHuPH20 [US]);|
| Experimental: IV treatment with IGSC, 10% only<br>Partial efficacy (trough levels of immunoglobulin G [IgG] only) and safety of intravenous (IV) administration of IGSC, 10% only. This was for participants enrolled in the study who had anti-rHuPH20 andibody titer from study160603 | Biological: IV treatment with IGSC, 10%<br>* During this safety follow-up period, participants are treated with IGSC, 10% via the intravenous (IV) route.<br>* Other names: KIOVIG (EU);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Rate of Serious Bacterial Infections | The point estimate of the annual rate of validated acute serious bacterial infections (VASBIs) per participant per year was provided during subcutaneous (SC) administration of Immune Globulin Subcutaneous Solution (IGSC), 10%, after SC administration of human recombinant hyaluronidase (rHuPH20). This efficacy outcome measure was only applicable prior to the safety follow-up i.e. before discontinuation of rHuPH20. | Throughout the efficacy period only (from 60 to 729 days) | 
| Annual Rate of All Infections | Annualized rate of infections per participant as defined by MedDRA system organ class (SOC) infections and infestations. The point estimate of the annual rate of all infections was provided during subcutaneous (SC) administration of Immune Globulin Subcutaneous Solution (IGSC), 10%, after SC administration of human recombinant hyaluronidase (rHuPH20). This efficacy outcome measure was only applicable prior to the safety follow-up i.e. before discontinuation of rHuPH20. | Throughout the efficacy period only (from 60 to 729 days) | 
| Trough Levels of IgG Maintained During the Study Period in Relation to Dose Frequency | Immunoglobulin (IgG) steady state trough levels were measured in relation to dose frequency by measuring in relation to treatment interval (2-, 3- or 4-week intervals). Initially participants were administered subcutaneous (SC) infusions of Immune Globulin Subcutaneous Solution (IGSC), 10%, after SC administration of human recombinant hyaluronidase (rHuPH20) [or IV infusions of IGSC, 10% only] at the treatment intervals and dose determined by epoch 2 of study 160603 (3- or 4-week intervals). After 3 treatment intervals (either 3- or 4- week intervals), participants changed to a 2-week treatment interval, if agreed with participant and investigator, with the dose adjusted to 1/2 of the 4-week dose or 2/3 of the 3-week dose, whichever was applicable. The rHuPH20 dose was adjusted relative to the new IGSC, 10% dose in order to achieve a dose ratio of 75 U/g IgG. This efficacy outcome measure was only applicable prior to the safety follow-up i.e. before discontinuation of rHuPH20. | Throughout the efficacy period only (from 60 to 729 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Annual Rate of Serious Adverse Events (SAEs), Related and Not Related to Study Drugs | Separated into age groups as described below and into related (related to either study drug) and not related (not related to either or both study drugs). Study drugs are Immune Globulin Subcutaneous Solution (IGSC), 10% and recombinant human hyaluronidase (rHuPH20). | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Percentage of Infusions for Which the Infusion Rate Was Reduced and/or the Infusion Interrupted or Stopped for Tolerability Concerns or for AEs |  | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Percentage of Infusions Associated With One or More Moderate or Severe AEs (Including and Excluding Infections) That Begin During or Within 72 Hours of Completion of an Infusion |  | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Number of Participants Who Develop Antibodies and Neutralizing Antibodies to rHuPH20 | Participants who develop binding antibodies and/or neutralizing antibodies to recombinant human hyaluronidase (rHuPH20) from study 160603 and/ or from this study (160902) are included here. This study (160902) is an extension of study 160603. Study 160603 was divided into 2 study epochs. In epoch 1 of study 160603 participants were treated with intravenous (IV) administration of Immune Globulin Subcutaneous Solution (IGSC), 10%. In epoch 2 of study 160603 participants were treated with subcutaneous (SC) administration of IGSC, 10% after SC administration of rHuPH20. Only participants who completed study 160603 were eligible to be screened and enrolled in this study (160902). In this study, participants started on same doses of IGSC, 10% and rHuPH20 that were used for the last infusions in epoch 2 of study 160603. | Throughout entire study period for 160603 (1 year 11 months) and 160902 (2 years 11 months) | 
| Percentage of Participants Who Develop Antibodies and Neutralizing Antibodies to rHuPH20 | Participants who develop binding antibodies and/or neutralizing antibodies to recombinant human hyaluronidase (rHuPH20) from study 160603 and/ or from this study (160902) are included here. This study (160902) is an extension of study 160603. Study 160603 was divided into 2 study epochs. In epoch 1 of study 160603 participants were treated with intravenous (IV) administration of Immune Globulin Subcutaneous Solution (IGSC), 10%. In epoch 2 of study 160603 participants were treated with subcutaneous (SC) administration of IGSC, 10% after SC administration of rHuPH20. Only participants who completed study 160603 were eligible to be screened and enrolled in this study (160902). In this study, participants started on same doses of IGSC, 10% and rHuPH20 that were used for the last infusions in epoch 2 of study 160603. | Throughout entire study period for 160603 (1 year 11 months) and 160902 (2 years 11 months) | 
| Number of Participants With AEs Related to Anti-rHuPH20 Titers |  | Throughout entire study period for 160603 (1 year 11 months) and 160902 (2 years 11 months) | 
| Percentage of Participants With AEs Related to Anti-rHuPH20 Titers |  | Throughout entire study period for 160603 (1 year 11 months) and 160902 (2 years 11 months) | 
| Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to the Study Drug, and Severity (A-F). | Categories presented as Preferred Term-Seriousness-Relatedness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Relatedness to study drug: R (related to either study drug); NR (not related to either or both study drugs). Study drugs are Immune Globulin Subcutaneous Solution, 10% (IGSC, 10%) and recombinant human hyaluronidase (rHuPH20) Severity: Mild; Mod (Moderate); Severe Preferred terms abbreviated: ADHD - Attention Deficit/Hyperactivity Disorder COPD - Chronic Obstructive Pulmonary Disease Other abbreviations: CPK - Creatinine Phosphokinase Inc. - Increased Dis - Disease Sml- small | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to the Study Drug, and Severity (G-M). | Categories presented as Preferred Term-Seriousness-Relatedness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Relatedness to study drug: R (related to either study drug); NR (not related to either or both study drugs). Study drugs are Immune Globulin Subcutaneous Solution, 10% (IGSC, 10%) and recombinant human hyaluronidase (rHuPH20) Severity: Mild; Mod (Moderate); Severe | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to the Study Drug, and Severity (N-Z). | Categories presented as Preferred Term-Seriousness, Relatedness, Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Relatedness to study drug: R (related to either study drug); NR (not related to either or both study drugs). Study drugs are Immune Globulin Subcutaneous Solution, 10% (IGSC, 10%) and recombinant human hyaluronidase (rHuPH20) Severity: Mild; Mod (Moderate); Severe Preferred terms abbreviated: Infection - Inf. | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of All AEs Per Participant Categorized by MedDRA Preferred Terms, Seriousness and Severity (A-F). | Categories presented as Preferred Term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe) Preferred terms abbreviated: ADHD - Attention Deficit/Hyperactivity Disorder COPD - Chronic Obstructive Pulmonary Disease Other abbreviations: Inc. - Increased Dis. - Disease | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of All AEs Per Participant Categorized by MedDRA Preferred Terms, Seriousness and Severity (G-M). | Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe) | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of All AEs Per Participant Categorized by MedDRA Preferred Terms, Seriousness and Severity (N-Z). | Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe) | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of All AEs Per Infusion Categorized by MedDRA Preferred Terms, Seriousness and Severity (A-F). | Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious adverse event; SAE- serious adverse event Severity: Mild; Mod (Moderate); Sev (Severe) Preferred terms abbreviated: ADHD - Attention Deficit/Hyperactivity Disorder COPD - Chronic Obstructive Pulmonary Disease Other abbreviations: Inc. - Increased Dis. - Disease | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of All AEs Per Infusion Categorized by MedDRA Preferred Terms, Seriousness and Severity (G-M). | Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe) | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of All AEs Per Infusion Categorized by MedDRA Preferred Terms, Seriousness and Severity (N-Z). | Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe) | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of AEs Per Participant (Including and Excluding Infections) Determined by the Investigator to be Related to the Study Drug That Occur at Any Time During the Study (Related) | Categories presented as adverse event (AE) type : Total, Local, Systemic including infections, Systemic excluding infections, and Severity (Mild, Moderate, Severe, Total). All of these adverse events are non-serious AEs. | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of AEs Per Infusion (Including and Excluding Infections) Determined by the Investigator to be Related to the Study Drug That Occur at Any Time During the Study (Related) | Categories presented as adverse event (AE) type : Total, Local, Systemic including infections, Systemic excluding infections, and Severity (Mild, Moderate, Severe, Total). All of these adverse events are non-serious AEs. | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of AEs Per Participant (Including and Excluding Infections) Temporarily Associated With the Infusion | Categories presented as adverse event (AE) type : Total, Local, Systemic including infections, Systemic excluding infections, Seriousness: Serious AE (SAE), non-serious AE (nsAE) and Severity (Mild, Moderate, Severe, Total). All of these adverse events are non-serious AEs. | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Rate of AEs Per Infusion (Including and Excluding Infections) Temporarily Associated With the Infusion | Categories presented as adverse event (AE) type : Total, Local, Systemic including infections, Systemic excluding infections, Seriousness: Serious AE (SAE), non-serious AE (non-SAE) and Severity (Mild, Moderate, Severe, Total). All of these adverse events are non-serious AEs. | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. | 
| Percentage of Infusions Associated With One or More Local AEs (Including and Excluding Infections), at Any Time During the Study |  | Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. |