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

Phase 2

Completed

Conditions: Primary Immunodeficiency Diseases (PID)

Registration Number: NCT00546871

Lead Sponsor: Baxalta now part of Shire

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 49

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
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	Week 12 (IV) and week 32 or 33 (SC)	Expressed as (AUC_SC/AUC_IV) \* 100
Bioavailability (Trough Levels) of IgG After Administration of IGIV, 10%, in Participants Aged 2 to <12 Years.	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	Administration of IGIV, 10%: - Part 1 = IV administration (IV) - Parts 2, 3a, 3b = SC administration (SC)
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	Throughout study (1 year and 9 months)	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
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.	Throughout study (1 year and 9 months)	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
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	Throughout study (1 year and 9 months)	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
Percentage of Infusions in FSDS for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped	Throughout study (1 year and 9 months)	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
Percentage of Infusions in SNSC for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped	Throughout study (1 year and 9 months)	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
Percentage of Infusions in SESC for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped	Throughout study (1 year and 9 months)	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

Secondary Outcome Measures

Name	Time	Method
Study Part 1 (IV): Maximum Plasma Concentration (C-max)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion.	Maximal immune globulin concentration after infusion
Study Part 1 (IV): Minimum Plasma Concentration (C-min)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion.	Minimal immune globulin concentration after infusion
Study Part 1 (IV): Weight-adjusted Clearance	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion.	Computed as weight-adjusted dose divided by total AUC
Study Part 1 (IV): Terminal Half-life	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion.	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.
Study Part 2 (Subcutaneous (SC)): Maximum Plasma Concentration (C-max)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	Maximal immune globulin concentration after infusion
Study Part 2 (SC): Time to Maximum Immune Globulin Concentration (T-max)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	Time to reach C-max
Study Part 2 (SC): Minimum Plasma Concentration (C-min)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	Minimal immune globulin concentration after infusion
Study Part 2 (SC): Weight-adjusted Clearance	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	Computed as weight-adjusted dose divided by total AUC
Study Part 3B: Maximum Plasma Concentration (C-max)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	Maximal immune globulin concentration after infusion
Study Part 3B: Time to Maximum Immune Globulin Concentration (T-max)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	Time to reach C-max
Study Part 3B: Minimum Plasma Concentration (C-min)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	Minimal immune globulin concentration after infusion
Proportion of Participants Reporting ≥1 Temporally Associated Moderate or Severe AEs	During Infusion or Within 72 Hours of Completion of Infusions	Proportion of Participants Reporting 1 or More Moderate or Severe AEs That Begin During Infusion or Within 72 Hours of Completion of an Infusion.
Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (FSDS)	Throughout entire study (1 year and 9 months)	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 All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (FSDS)	Throughout entire study (1 year and 9 months)	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.
Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SNSC -All Ages)	Throughout entire study (1 year and 9 months)	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 All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SNSC- All Ages)	Throughout entire study (1 year and 9 months)	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.
Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SESC)	Throughout entire study (1 year and 9 months)	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 All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SESC)	Throughout entire study (1 year and 9 months)	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.
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
Study Part 3B: Area Under the Curve (AUC)	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	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).
Study Part 3B: Weight-adjusted Clearance	Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.	Computed as weight-adjusted dose divided by total AUC
Trough Levels of IgG After Administration of IGIV, 10%, in Participants 12 Years and Older	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	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)
Trough Levels of Antibody to Haemophilus Influenzae In All Study Participants	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 for IV and SC Treatment in Study Parts 1, 2, 3a and 3b.
Trough Levels of Antibody to Hepatitis B in All Study Participants	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 for IV and SC Treatment in Study Parts 1, 2, 3a and 3b.
Trough Levels of Antibody to Tetanus In All Study Participants	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 for IV and SC Treatment in Study Parts 1, 2, 3a and 3b.
Number of Anti-Measles Antibody Titers That Were Below or Above the Protective Titer Level	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	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.
Annual Infection Rates During Treatment	Throughout the study, 1 year and 9 months	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.
Annual Rate of Acute Serious Bacterial Infections During IV and SC Treatment (FSDS)	Throughout the study, 1 year and 9 months	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.
Rate of Temporally Associated AEs Per Infusion	During Infusion or Within 72 Hours of Completion of Infusions	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.
AEs Deemed/Judged to be Related by the Investigator	Throughout the study period (1 year and 9 months)	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.
Frequency of Dose Adjustments (If IgG Trough Levels <4.5 g/L)	Throughout the study period (1 year and 9 months)	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.
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