Clinical trial NCT00546871: Comparison of Intravenous and Subcutaneous Administration of IGIV, 10% in Primary Immunodeficiency (PID) Subjects
Official title: Tolerability and Pharmacokinetic Comparison of Immune Globulin Intravenous (Human) 10% (IGIV, 10%) Administered Intravenously or Subcutaneously in Subjects With Primary Immunodeficiency Diseases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Primary Immunodeficiency Diseases (PID)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2007-10-19
Enrollment: 49
Sex: ALL
Minimum age (years): 24
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: 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
timeFrame: Week 12 (IV) and week 32 or 33 (SC)
measure: Bioavailability (Trough Levels) of IgG After Administration of IGIV, 10%, in Participants Aged 2 to <12 Years.
timeFrame: 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
measure: 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
timeFrame: Throughout study (1 year and 9 months)
measure: 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.
timeFrame: Throughout study (1 year and 9 months)
measure: 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
timeFrame: Throughout study (1 year and 9 months)
measure: Percentage of Infusions in FSDS for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped
timeFrame: Throughout study (1 year and 9 months)
measure: Percentage of Infusions in SNSC for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped
timeFrame: Throughout study (1 year and 9 months)
measure: Percentage of Infusions in SESC for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped
timeFrame: Throughout study (1 year and 9 months)
Secondary outcomes:
measure: Study Part 1 (IV): Maximum Plasma Concentration (C-max)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion.
measure: Study Part 1 (IV): Minimum Plasma Concentration (C-min)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion.
measure: Study Part 1 (IV): Weight-adjusted Clearance
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion.
measure: Study Part 1 (IV): Terminal Half-life
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #3 starts) up to 28 days (+/-2 days) post-infusion.
measure: Study Part 2 (Subcutaneous (SC)): Maximum Plasma Concentration (C-max)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Study Part 2 (SC): Time to Maximum Immune Globulin Concentration (T-max)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Study Part 2 (SC): Minimum Plasma Concentration (C-min)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Study Part 2 (SC): Weight-adjusted Clearance
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Study Part 3B: Maximum Plasma Concentration (C-max)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Study Part 3B: Time to Maximum Immune Globulin Concentration (T-max)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Study Part 3B: Minimum Plasma Concentration (C-min)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Study Part 3B: Area Under the Curve (AUC)
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Study Part 3B: Weight-adjusted Clearance
timeFrame: Pharmacokinetic evaluations: 60 minutes pre-infusion (before infusion #8 starts) up to 7 days (+/-1 day) post-infusion.
measure: Trough Levels of IgG After Administration of IGIV, 10%, in Participants 12 Years and Older
timeFrame: 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
measure: Trough Levels of Antibody to Haemophilus Influenzae In All Study Participants
timeFrame: 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
measure: Trough Levels of Antibody to Hepatitis B in All Study Participants
timeFrame: 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
measure: Trough Levels of Antibody to Tetanus In All Study Participants
timeFrame: 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
measure: Number of Anti-Measles Antibody Titers That Were Below or Above the Protective Titer Level
timeFrame: 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
measure: Annual Infection Rates During Treatment
timeFrame: Throughout the study, 1 year and 9 months
measure: Annual Rate of Acute Serious Bacterial Infections During IV and SC Treatment (FSDS)
timeFrame: Throughout the study, 1 year and 9 months
measure: Rate of Temporally Associated AEs Per Infusion
timeFrame: During Infusion or Within 72 Hours of Completion of Infusions
measure: AEs Deemed/Judged to be Related by the Investigator
timeFrame: Throughout the study period (1 year and 9 months)
measure: Frequency of Dose Adjustments (If IgG Trough Levels <4.5 g/L)
timeFrame: Throughout the study period (1 year and 9 months)
measure: Proportion of Participants Reporting ≥1 Temporally Associated Moderate or Severe AEs
timeFrame: During Infusion or Within 72 Hours of Completion of Infusions
measure: Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (FSDS)
timeFrame: Throughout entire study (1 year and 9 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (FSDS)
timeFrame: Throughout entire study (1 year and 9 months)
measure: Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SNSC -All Ages)
timeFrame: Throughout entire study (1 year and 9 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SNSC- All Ages)
timeFrame: Throughout entire study (1 year and 9 months)
measure: Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SESC)
timeFrame: Throughout entire study (1 year and 9 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Severity, and Causality (SESC)
timeFrame: Throughout entire study (1 year and 9 months)
measure: Percentage of Infusions Associated With ≥1 AE Related to the Study Drug
timeFrame: Throughout the study period (1 year and 9 months)
measure: Percentage of Infusions Associated With ≥1 AEs That Begin During Infusion or Within 72 Hours of Completion of Infusion
timeFrame: During Infusion or Within 72 Hours of Completion of Infusions
measure: Percentage of Infusions Associated With ≥1 AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion.
timeFrame: During Infusion or Within 72 Hours of Completion of Infusions
measure: Percentage of Infusions Associated With ≥1 Systemic AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion.
timeFrame: During Infusion or Within 72 Hours of Completion of Infusions
measure: Percentage of Infusions Associated With ≥1 Local AE Excluding Infections That Begin During Infusion or Within 72 Hours of Completion of Infusion.
timeFrame: During Infusion or Within 72 Hours of Completion of Infusions
Other outcomes:
Locations:
city: Los Angeles
country: United States
state: California
city: Centennial
country: United States
state: Colorado
city: North Palm Beach
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Durham
country: United States
state: North Carolina
city: Cleveland
country: United States
state: Ohio
city: Dallas
country: United States
state: Texas
city: Galveston
country: United States
state: Texas
city: Milwaukee
country: United States
state: Wisconsin
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Neu AM, Warady BA, Furth SL, Lederman HM, Fivush BA. Antibody levels to diphtheria, tetanus, and rubella in infants vaccinated while on PD: a Study of the Pediatric Peritoneal Dialysis Study Consortium. Adv Perit Dial. 1997;13:297-9.
citation: Leibl H, Engl W, Melamed I, Stein M, Wasserman RL, Berger M, Schiff RI. IGIV-10% Infused Intravenously And Subcutaneously To Subjects With Primary Immunodeficiency Diseases - Comparison Of Pharmacokinetic Properties. Poster presentation at AAAAI 2009.
citation: Schiff RI, Leibl H, Engl W. Pharmacokinetic properties of Gammagard Liquid 10% (KIOVIG) administered intravenously and subcutaneously to patients with primary immunodeficiency diseases. Clin Exp Immunol. 154 (Suppl. 1):132, 2008
citation: Wasserman RL, Melamed I, Kobrynski L, Strausbaugh SD, Stein MR, Sharkhawy M, Engl W, Leibl H, Sobolevsky L, Gelmont D, Schiff RI, Grossman WJ. Efficacy, safety, and pharmacokinetics of a 10% liquid immune globulin preparation (GAMMAGARD LIQUID, 10%) administered subcutaneously in subjects with primary immunodeficiency disease. J Clin Immunol. 2011 Jun;31(3):323-31. doi: 10.1007/s10875-011-9512-z. Epub 2011 Mar 22.
citation: Wasserman RL, Gupta S, Stein M, Rabbat CJ, Engl W, Leibl H, Yel L. Infection rates and tolerability of three different immunoglobulin administration modalities in patients with primary immunodeficiency diseases. Immunotherapy. 2022 Mar;14(4):215-224. doi: 10.2217/imt-2021-0256. Epub 2021 Dec 21.