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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Baxter Healthcare Corporation
ClinicalTrials.gov Identifier:
NCT00546871
First received: October 18, 2007
Last updated: September 19, 2012
Last verified: September 2012
  Purpose

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.


Condition Intervention Phase
Primary Immunodeficiency (PID)
Drug: Immune Globulin Intravenous (Human), 10%
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Tolerability and Pharmacokinetic Comparison of Immune Globulin Intravenous (Human) 10% (IGIV, 10%) Administered Intravenously or Subcutaneously in Subjects With Primary Immunodeficiency Diseases

Further study details as provided by Baxter Healthcare Corporation:

Primary Outcome Measures:
  • 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 [ Time Frame: Week 12 (IV) and week 32 or 33 (SC) ] [ Designated as safety issue: No ]
    Expressed as (AUC_SC/AUC_IV) * 100

  • Bioavailability (Trough Levels) of IgG After Administration of IGIV, 10%, in Participants Aged 2 to <12 Years. [ Time Frame: 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 ] [ Designated as safety issue: No ]

    Administration of IGIV, 10%:

    • Part 1 = IV administration (IV)
    • Parts 2, 3a, 3b = SC administration (SC)

  • 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 [ Time Frame: Throughout study (1 year and 9 months) ] [ Designated as safety issue: Yes ]
    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. [ Time Frame: Throughout study (1 year and 9 months) ] [ Designated as safety issue: Yes ]
    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 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 [ Time Frame: Throughout study (1 year and 9 months) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Throughout study (1 year and 9 months) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Throughout study (1 year and 9 months) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Throughout study (1 year and 9 months) ] [ Designated as safety issue: Yes ]
    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:
  • Study Part 1 (IV): Maximum Plasma Concentration (C-max) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion. ] [ Designated as safety issue: No ]
    Maximal immune globulin concentration after infusion

  • Study Part 1 (IV): Minimum Plasma Concentration (C-min) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion. ] [ Designated as safety issue: No ]
    Minimal immune globulin concentration after infusion

  • Study Part 1 (IV): Weight-adjusted Clearance [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion. ] [ Designated as safety issue: No ]
    Computed as weight-adjusted dose divided by total AUC

  • Study Part 1 (IV): Terminal Half-life [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion. ] [ Designated as safety issue: No ]
    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) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    Maximal immune globulin concentration after infusion

  • Study Part 2 (SC): Time to Maximum Immune Globulin Concentration (T-max) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    Time to reach C-max

  • Study Part 2 (SC): Minimum Plasma Concentration (C-min) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    Minimal immune globulin concentration after infusion

  • Study Part 2 (SC): Weight-adjusted Clearance [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    Computed as weight-adjusted dose divided by total AUC

  • Study Part 3B: Maximum Plasma Concentration (C-max) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    Maximal immune globulin concentration after infusion

  • Study Part 3B: Time to Maximum Immune Globulin Concentration (T-max) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    Time to reach C-max

  • Study Part 3B: Minimum Plasma Concentration (C-min) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    Minimal immune globulin concentration after infusion

  • Study Part 3B: Area Under the Curve (AUC) [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    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 [ Time Frame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion. ] [ Designated as safety issue: No ]
    Computed as weight-adjusted dose divided by total AUC

  • Trough Levels of IgG After Administration of IGIV, 10%, in Participants 12 Years and Older [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Throughout the study, 1 year and 9 months ] [ Designated as safety issue: No ]
    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) [ Time Frame: Throughout the study, 1 year and 9 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: During Infusion or Within 72 Hours of Completion of Infusions ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Throughout the study period (1 year and 9 months) ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Throughout the study period (1 year and 9 months) ] [ Designated as safety issue: Yes ]

    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.


  • Proportion of Participants Reporting ≥1 Temporally Associated Moderate or Severe AEs [ Time Frame: During Infusion or Within 72 Hours of Completion of Infusions ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Throughout entire study (1 year and 9 months) ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: Throughout entire study (1 year and 9 months) ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: Throughout entire study (1 year and 9 months) ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: Throughout entire study (1 year and 9 months) ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: Throughout entire study (1 year and 9 months) ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: Throughout entire study (1 year and 9 months) ] [ Designated as safety issue: Yes ]

    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 [ Time Frame: Throughout the study period (1 year and 9 months) ] [ Designated as safety issue: Yes ]
  • Percentage of Infusions Associated With ≥1 AEs That Begin During Infusion or Within 72 Hours of Completion of Infusion [ Time Frame: During Infusion or Within 72 Hours of Completion of Infusions ] [ Designated as safety issue: Yes ]
  • Percentage of Infusions Associated With ≥1 AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion. [ Time Frame: During Infusion or Within 72 Hours of Completion of Infusions ] [ Designated as safety issue: Yes ]
  • Percentage of Infusions Associated With ≥1 Systemic AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion. [ Time Frame: During Infusion or Within 72 Hours of Completion of Infusions ] [ Designated as safety issue: Yes ]
  • Percentage of Infusions Associated With ≥1 Local AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion. [ Time Frame: During Infusion or Within 72 Hours of Completion of Infusions ] [ Designated as safety issue: Yes ]

Enrollment: 49
Study Start Date: October 2007
Study Completion Date: September 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Immune Globulin Intravenous (Human), 10%
    Intravenous administration in Study Part 1, subcutaneous administration in Study Parts 2 and 3
  Eligibility

Ages Eligible for Study:   24 Months and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00546871

Locations
United States, California
Los Angeles, California, United States
United States, Colorado
Centennial, Colorado, United States
United States, Florida
North Palm Beach, Florida, United States
United States, Georgia
Atlanta, Georgia, United States
United States, North Carolina
Durham, North Carolina, United States
United States, Ohio
Cleveland, Ohio, United States
United States, Texas
Dallas, Texas, United States
Galveston, Texas, United States
United States, Wisconsin
Milwaukee, Wisconsin, United States
Sponsors and Collaborators
Baxter Healthcare Corporation
Investigators
Study Director: Baxter BioScience Investigator Baxter Healthcare Corporation
  More Information

Publications:
Responsible Party: Baxter Healthcare Corporation
ClinicalTrials.gov Identifier: NCT00546871     History of Changes
Other Study ID Numbers: 160601
Study First Received: October 18, 2007
Results First Received: November 15, 2011
Last Updated: September 19, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Immune System Diseases
Antibodies
Immunoglobulins
Immunoglobulins, Intravenous
Rho(D) Immune Globulin
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 23, 2014