Comparison of Intravenous and Subcutaneous Administration of IGIV, 10% in Primary Immunodeficiency (PID) Subjects

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the tolerability of IGIV, 10% given subcutaneously and the pharmacokinetics of immunoglobulin G (IgG) following subcutaneous (SC) treatment with IGIV, 10% in subjects with primary immunodeficiency (PID) disorders.

Official Title
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Tolerability and Pharmacokinetic Comparison of Immune Globulin Intravenous (Human) 10% (IGIV, 10%) Administered Intravenously or Subcutaneously in Subjects With Primary Immunodeficiency Diseases

Conditions
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Primary Immunodeficiency Diseases (PID)

Intervention / Treatment
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* Drug: Immune Globulin Intravenous (Human), 10%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained from either the subject or the subject's legally acceptable representative prior to any study-related procedures and study product administration Diagnosis of a PID disorder as defined by World Health Organization criteria (IUIS Scientific Committee, Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. Clin Exp Immunol. 1999) for which the subject has been receiving a regular regimen of IV immunoglobulin infusions every 21 ± 3 days or 28 ± 3 days or a regular SC immunoglobulin treatment at 1 to 2 week intervals over a period of at least 3 months pre-study at a dose of 300-800 mg/kg BW/4 weeks Subjects are aged 2 years or older Subjects have a serum trough level of IgG > 4.5 g/L at the last documented determination A negative serum pregnancy test for any female subject who is of childbearing potential Female subjects of childbearing potential agree to practice birth control measures for the duration of the study Exclusion Criteria: Subjects positive at enrollment for one or more of the following: Hepatitis B surface antigen (HBsAg), PCR for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1 Subjects with levels of alanine amino transferase (ALT) or aspartate amino transferase (AST) > 2.5 times the upper limit of normal for the testing laboratory Subjects with neutropenia (defined as an absolute neutrophil count [ANC] <= 500/mm3) Subjects with serum creatinine levels greater than 1.5 times the upper limit of normal for age and gender Subjects with a malignancy other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix Subjects with a history of thrombotic episodes (deep vein thrombosis, myocardial infarction, cerebrovascular accident) Subjects with abnormal protein loss (protein losing enteropathy, nephritic syndrome, severe lung disease) Subjects with anemia that would preclude phlebotomy for laboratory studies Subjects who received any blood or blood product other than an IGIV, SC immunoglobulin, immune serum globulin (ISG) preparation, or albumin within the 6 months prior to study enrollment Subjects with an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IGIV, SC immunoglobulin and/or ISG infusions Subjects with IgA deficiency and known anti IgA antibodies Subjects receiving antibiotic therapy for the treatment of infection within 7 days prior to enrollment Subjects participating in another clinical study involving an investigational product or device within 28 days prior to study enrollment Subjects with bleeding disorders or who are on anti-coagulation therapy

Ages Eligible for Study
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Minimum Age: 24 Months

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Immune Globulin Intravenous (Human), 10%|Intravenous administration in Study Part 1, subcutaneous administration in Study Parts 2 and 3|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of Area Under the Concentration Curve (AUC 0-τ)/Week Following IV Administration to SC Administration of IGIV, 10% at an Adjusted/Individual Adapted Dose (Part 3b), Expressed as a Percentage | Expressed as (AUC_SC/AUC_IV) * 100 | Week 12 (IV) and week 32 or 33 (SC) | 
| Bioavailability (Trough Levels) of IgG After Administration of IGIV, 10%, in Participants Aged 2 to <12 Years. | Administration of IGIV, 10%: - Part 1 = IV administration (IV) - Parts 2, 3a, 3b = SC administration (SC) | Baseline; at each 3 or 4-week study visit in Study Part 1; at Visits 1, 5, and 9 in Study Part 2; at Visits 1, and 5 in Study Part 3a; at Visits 1, 5, and 9 in Study Part 3b; and at the end-of-study evaluation | 
| Percentage of Participants in Full Safety Data Set (FSDS) Who Had Any Infusion for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped | Ability to tolerate IGIV, 10% administered IV or SC. Measured as the percentage of participants for which the infusion rate was reduced at any infusion and/or the infusion was interrupted or stopped for (i) any reason and (ii) for tolerability concerns or AEs | Throughout study (1 year and 9 months) | 
| Percentage of Participants Naïve to SC Administration of Immunoglobulins (SNSC) Who Had Any Infusion for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped. | Ability to tolerate IGIV, 10% administered IV or SC. Measured as the percentage of participants for which the infusion rate was reduced at any infusion and/or the infusion was interrupted or stopped for (i) any reason and (ii) for tolerability concerns or AEs | Throughout study (1 year and 9 months) | 
| Percentage of Participants With Prior Experience With Subcutaneous Administration of Immunoglobulins (SESC) Who Had Any Infusion for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped | Ability to tolerate IGIV, 10% administered IV or SC. Measured as the percentage of participants for which the infusion rate was reduced at any infusion and/or the infusion was interrupted or stopped for (i) any reason and (ii) for tolerability concerns or AEs | Throughout study (1 year and 9 months) | 
| Percentage of Infusions in FSDS for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped | Ability to tolerate IGIV, 10% administered IV or SC. Measured as the percentage of infusions for which the infusion rate was reduced at any infusion and/or the infusion was interrupted or stopped for (i) any reason and (ii) for tolerability concerns or AEs | Throughout study (1 year and 9 months) | 
| Percentage of Infusions in SNSC for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped | Ability to tolerate IGIV, 10% administered IV or SC. Measured as the percentage of infusions for which the infusion rate was reduced at any infusion and/or the infusion was interrupted or stopped for (i) any reason and (ii) for tolerability concerns or AEs | Throughout study (1 year and 9 months) | 
| Percentage of Infusions in SESC for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped | Ability to tolerate IGIV, 10% administered IV or SC. Measured as the percentage of infusions for which the infusion rate was reduced at any infusion and/or the infusion was interrupted or stopped for (i) any reason and (ii) for tolerability concerns or AEs | Throughout study (1 year and 9 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study Part 1 (IV): Maximum Plasma Concentration (C-max) | Maximal immune globulin concentration after infusion | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion. | 
| Study Part 1 (IV): Minimum Plasma Concentration (C-min) | Minimal immune globulin concentration after infusion | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion. | 
| Study Part 1 (IV): Weight-adjusted Clearance | Computed as weight-adjusted dose divided by total AUC | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion. | 
| Study Part 1 (IV): Terminal Half-life | Computed from the regression slope in the terminal phase of the model (the slope is biphasic). Terminal half life is the time it takes for the plasma concentration or the amount of immunoglobulin in the body to be reduced by 50%during the terminal phase. | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion. | 
| Study Part 2 (Subcutaneous (SC)): Maximum Plasma Concentration (C-max) | Maximal immune globulin concentration after infusion | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Study Part 2 (SC): Time to Maximum Immune Globulin Concentration (T-max) | Time to reach C-max | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Study Part 2 (SC): Minimum Plasma Concentration (C-min) | Minimal immune globulin concentration after infusion | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Study Part 2 (SC): Weight-adjusted Clearance | Computed as weight-adjusted dose divided by total AUC | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Study Part 3B: Maximum Plasma Concentration (C-max) | Maximal immune globulin concentration after infusion | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Study Part 3B: Time to Maximum Immune Globulin Concentration (T-max) | Time to reach C-max | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Study Part 3B: Minimum Plasma Concentration (C-min) | Minimal immune globulin concentration after infusion | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Study Part 3B: Area Under the Curve (AUC) | The AUC between adjacent infusions was calculated by the trapezoidal rule. Linear interpolation/extrapolation was used to calculate the AUC for the exact duration of the infusion intervals (21 or 28 days for IV administration and 7 days for SC administration). To allow for comparisons between Study Parts 1, 2 and 3b, AUC(0-τ) was standardized for the infusion intervals (3 or 4 weeks vs. 1 week). | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Study Part 3B: Weight-adjusted Clearance | Computed as weight-adjusted dose divided by total AUC | Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. | 
| Trough Levels of IgG After Administration of IGIV, 10%, in Participants 12 Years and Older | Part 1: IgG trough levels measured at each IV infusion day (every 3rd or 4th week depending on schedule/frequency of participants for a total of 12 weeks) Part 2: IgG trough levels measured at weeks 1, 5 and 9 (of a total of 12 weeks) Part 3a: IgG trough levels measured at weeks 1 and 5 (of a total of 6 weeks) Part 3b: IgG trough levels measured at weeks 1, 5, 9 and 12 (of a total of 12 weeks) | Baseline; at each 3 or 4-week study visit in Study Part 1; at Visits 1, 5, and 9 in Study Part 2; at Visits 1, and 5 in Study Part 3a; at Visits 1, 5, and 9 in Study Part 3b; and at the end-of-study evaluation | 
| Trough Levels of Antibody to Haemophilus Influenzae In All Study Participants | Trough levels for IV and SC Treatment in Study Parts 1, 2, 3a and 3b. | Baseline; at each 3 or 4-week study visit in Study Part 1; at Visits 1, 5, and 9 in Study Part 2; at Visit 1 in Study Part 3a; at Visits 1, 5, and 9 in Study Part 3b; at Visit 1 in the Study Extension Part; and at the end-of-study evaluation | 
| Trough Levels of Antibody to Hepatitis B in All Study Participants | Trough levels for IV and SC Treatment in Study Parts 1, 2, 3a and 3b. | Baseline; at each 3 or 4-week study visit in Study Part 1; at Visits 1, 5, and 9 in Study Part 2; at Visit 1 in Study Part 3a; at Visits 1, 5, and 9 in Study Part 3b; at Visit 1 in the Study Extension Part; and at the end-of-study evaluation | 
| Trough Levels of Antibody to Tetanus In All Study Participants | Trough levels for IV and SC Treatment in Study Parts 1, 2, 3a and 3b. | Baseline; at each 3 or 4-week study visit in Study Part 1; at Visits 1, 5, and 9 in Study Part 2; at Visit 1 in Study Part 3a; at Visits 1, 5, and 9 in Study Part 3b; at Visit 1 in the Study Extension Part; and at the end-of-study evaluation | 
| Number of Anti-Measles Antibody Titers That Were Below or Above the Protective Titer Level | Antibody Titers That Were Below or Above the Protective Titer Level of >1:8 for IV and SC Treatment in Study Parts 1, 2, 3a and 3b. Participants had multiple anti-measles antibody titers measured during the study. | Baseline; at each 3 or 4-week study visit in Study Part 1; at Visits 1, 5, and 9 in Study Part 2; at Visit 1 in Study Part 3a; at Visits 1, 5, and 9 in Study Part 3b; at Visit 1 in the Study Extension Part; and at the end-of-study evaluation | 
| Annual Infection Rates During Treatment | Annual rate of all infections calculated using a Poisson model to account for different lengths of observation per subject using SAS V9.1.3 procedure GENMOD with allowance for overdispersion by deviance method. Point estimates and likelihood-ratio based 95% confidence intervals were provided. Infections as included in analysis comprised all reported AEs that were coded to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) of infections and infestations, described as an infection by investigator, or for which anti-infective medication was prescribed. | Throughout the study, 1 year and 9 months | 
| Annual Rate of Acute Serious Bacterial Infections During IV and SC Treatment (FSDS) | Annual rate of validated acute serious bacterial infections was calculated using a Poisson model to account for the different lengths of observation per subject using SAS V9.1.3 procedure GENMOD with an allowance for overdispersion by the deviance method. | Throughout the study, 1 year and 9 months | 
| Rate of Temporally Associated AEs Per Infusion | Rate of AEs per infusion defined as the total number of all AEs that begin during infusion or within 72 hours of completion of an infusion (temporally associated) divided by the total number of infusions. | During Infusion or Within 72 Hours of Completion of Infusions | 
| AEs Deemed/Judged to be Related by the Investigator | Rate of related AEs defined as the total number of AEs determined by the investigator to be related to the study drug that occur at any time during the study divided by the total number of infusions. | Throughout the study period (1 year and 9 months) | 
| Frequency of Dose Adjustments (If IgG Trough Levels <4.5 g/L) | Frequency of Dose Adjustments Based on IgG Trough Levels <4.5 g/L IgG, if Any, for Each Study Part. Defined/calculated as the number of participants requiring dose adjustments divided by the number of participants, for each respective data set. | Throughout the study period (1 year and 9 months) | 
| Proportion of Participants Reporting ≥1 Temporally Associated Moderate or Severe AEs | Proportion of Participants Reporting 1 or More Moderate or Severe AEs That Begin During Infusion or Within 72 Hours of Completion of an Infusion. | During Infusion or Within 72 Hours of Completion of Infusions | 
| Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (FSDS) | Seriousness and causality are abbreviated below as: Seriousness: Serious Adverse Event= SAE, non-Serious Adverse Event= non-SAE Causality: possibly or probably related= R, not related= NR | Throughout entire study (1 year and 9 months) | 
| Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (FSDS) | Seriousness and causality are abbreviated below as: Seriousness: Serious Adverse Event= SAE, non-Serious Adverse Event= non-SAE Causality: possibly or probably related= R, not related= NR Rate of AEs defined as the number of AEs categorized by MedDRA preferred terms, seriousness, severity, and causality divided by the number of infusions. | Throughout entire study (1 year and 9 months) | 
| Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SNSC -All Ages) | Seriousness and causality are abbreviated below as: Seriousness: Serious Adverse Event= SAE, non-Serious Adverse Event= non-SAE Causality: possibly or probably related= R, not related= NR | Throughout entire study (1 year and 9 months) | 
| Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SNSC- All Ages) | Seriousness and causality are abbreviated below as: Seriousness: Serious Adverse Event= SAE, non-Serious Adverse Event= non-SAE Causality: possibly or probably related= R, not related= NR Rate of AEs defined as the number of AEs categorized by MedDRA preferred terms, seriousness, severity, and causality divided by the number of infusions. | Throughout entire study (1 year and 9 months) | 
| Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SESC) | Seriousness and causality are abbreviated below as: Seriousness: Serious Adverse Event= SAE, non-Serious Adverse Event= non-SAE Causality: possibly or probably related= R, not related= NR | Throughout entire study (1 year and 9 months) | 
| Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SESC) | Seriousness and causality are abbreviated below as: Seriousness: Serious Adverse Event= SAE, non-Serious Adverse Event= non-SAE Causality: possibly or probably related= R, not related= NR Rate of AEs defined as the number of AEs categorized by MedDRA preferred terms, seriousness, severity, and causality divided by the number of infusions. | Throughout entire study (1 year and 9 months) | 
| Percentage of Infusions Associated With ≥1 AE Related to the Study Drug |  | Throughout the study period (1 year and 9 months) | 
| Percentage of Infusions Associated With ≥1 AEs That Begin During Infusion or Within 72 Hours of Completion of Infusion |  | During Infusion or Within 72 Hours of Completion of Infusions | 
| Percentage of Infusions Associated With ≥1 AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion. |  | During Infusion or Within 72 Hours of Completion of Infusions | 
| Percentage of Infusions Associated With ≥1 Systemic AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion. |  | During Infusion or Within 72 Hours of Completion of Infusions | 
| Percentage of Infusions Associated With ≥1 Local AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion. |  | During Infusion or Within 72 Hours of Completion of Infusions |