Study of Subcutaneous Immunoglobulin in Patients With PID Requiring IgG Replacement Therapy

• ClinicalTrials.gov Identifier: NCT00419341
• Recruitment Status: Completed
• First Posted: January 8, 2007
• Results First Posted: January 25, 2013
• Last Update Posted: January 25, 2013
• Sponsor: CSL Behring
• Information provided by (Responsible Party): CSL Behring

Study Description

Brief Summary:

The objective of this study is to assess the efficacy, tolerability, safety and pharmacokinetics of IgPro20 in patients with primary humoral immunodeficiency (PID).

Condition or disease	Intervention/treatment	Phase
Primary Immune Deficiency	Biological: Human Normal Immunoglobulin for Subcutaneous Administration	Phase 3

Detailed Description:

The entire study consists of a 12-week wash-in/wash-out period followed by a 12-month treatment period. Pharmacokinetic (PK) parameters were assessed in a sub-group of subjects.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 49 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Open-Label, Prospective, Multicenter Study of the Efficacy, Tolerability, Safety, and Pharmacokinetics of Immune Globulin Subcutaneous (Human), IgPro20 in Subjects With Primary Immunodeficiency (PID)
• Study Start Date: November 2006
• Actual Primary Completion Date: October 2008
• Actual Study Completion Date: October 2008

Arms and Interventions

Arm

Intervention/treatment

Experimental: IgPro20; Human Normal Immunoglobulin for Subcutaneous Administration (IgPro20) is a liquid formulation of normal human IgG at a concentration of 20% administered as a SC infusion at weekly intervals. The initial weekly dose was determined based on subjects' previous treatment. Dose adjustments could be performed during the wash-in/wash-out period at the discretion of the investigator.

Biological: Human Normal Immunoglobulin for Subcutaneous Administration; Other Name: Hizentra

Outcome Measures

Primary Outcome Measures :

1. Annualized Rate of Clinically Documented Serious Bacterial Infections (SBIs) (MITT Population) [ Time Frame: Efficacy period: up to 12 months (week 13 to the completion visit) ]

   The annualized rate was based on the total number of SBIs and the total number of subject study days during the efficacy period for all subjects in the specified analysis population and adjusted to 365 days.

   Potential SBIs included pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. If an adverse event (AE) was identified as a potential SBI, the AE was adjudicated by a review committee to determine if the event fulfilled the predefined criteria for SBIs.

2. Area Under the Concentration-time Curve (AUC) of Total Serum Immunoglobulin G (IgG) [ Time Frame: Measured during a single dosing interval after at least 12 weeks of stable subcutaneous (SC) dosing with IgPro20 treatment ]
   Evaluate non-inferiority of steady-state IgG area under the concentration-time curves standardized to a 7-day period (sAUCs) for subcutaneous immunoglobulin (SCIG) (IgPro20) versus the sAUC under intravenous immunoglobulin (IVIG) (Privigen) treatment. The sAUC under IVIG was taken from the same subjects in a preceding study (either ZLB03_002CR [NCT00168025] or ZLB05_006CR [NCT00322556]).

Secondary Outcome Measures :

1. Annualized Rate of Clinically Documented SBIs (ITT Population) [ Time Frame: For the duration of the study, up to 15 months ]

   The annualized rate was based on the total number of SBIs and the total number of subject study days during the study for all subjects in the specified analysis population and adjusted to 365 days.

   Potential SBIs included pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. If an AE was identified as a potential SBI, the AE was adjudicated by a review committee to determine if the event fulfilled the predefined criteria for SBIs.

2. Annualized Rate of Clinically Documented SBIs (PPE Population) [ Time Frame: Efficacy period: up to 12 months (week 13 to the completion visit) ]

   The annualized rate was based on the total number of SBIs and the total number of subject study days during the efficacy period for all subjects in the specified analysis population and adjusted to 365 days.

   Potential SBIs included pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. If an AE was identified as a potential SBI, the AE was adjudicated by a review committee to determine if the event fulfilled the predefined criteria for SBIs.

3. Annualized Rate of Infection Episodes [ Time Frame: Efficacy period: up to 12 months (week 13 to completion visit) ]
   The annualized rate was based on the total number of infection episodes occurring during the efficacy period (N = 96) divided by the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days.
4. Number of Infection Episodes (Serious and Non-serious) [ Time Frame: Efficacy period: up to 12 months (week 13 to the completion visit) ]
   Total number of infections for the specified analysis population
5. Annualized Rate of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections [ Time Frame: Efficacy period: up to 12 months (week 13 to the completion visit) ]
   The annualized rate was based on the total number of days out of work / school / kindergarten / day care or inability to perform normal activities due to infection (N = 71), and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days.
6. Number of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections [ Time Frame: Efficacy period: up to 12 months (week 13 to the completion visit) ]
   Total number of days out of work / school / kindergarten / day care or unable to perform normal daily activities due to infections, for the specified analysis population
7. Annualized Rate of Hospitalization Due to Infection [ Time Frame: Efficacy period: up to 12 months (week 13 to the completion visit) ]
   The annualized rate was based on the total number of days of hospitalization due to infection (N = 7) and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days.
8. Number of Days of Hospitalization Due to Infections [ Time Frame: Efficacy period: up to 12 months (week 13 to the completion visit) ]
   Total number of days of hospitalization due to infections for the specified analysis population
9. Use of Antibiotics for Infection Prophylaxis and Treatment [ Time Frame: Efficacy period: up to 12 months (week 13 to the completion visit) ]
   Annualized rate of days with antibiotics for infection prophylaxis and treatment. The annualized rate was based on the total number of days of antibiotic use for infection prophylaxis and treatment in the efficacy period, and the total number of subject study days for all subjects in the specified analysis population, and adjusted to 365 days.
10. Total Serum IgG Trough Levels [ Time Frame: Every 4 weeks, throughout the 12-month efficacy period ]
    The IgG trough values per subject were aggregated to a median value, and then median values across subjects were summarized using descriptive statistics.
11. Maximum Concentration (Cmax) of Total Serum IgG at Steady State [ Time Frame: Week 28 ± 1 week of the treatment period ]
12. Tmax at Steady State [ Time Frame: Week 28 ± 1 week of the treatment period ]
    Timepoint of maximum concentration (Cmax)

Other Outcome Measures:

1. Minimum Concentration (Cmin) of Total Serum IgG at Steady State [ Time Frame: Week 28 ± 1 week of the treatment period ]
2. Rate of All AEs by Relatedness and Seriousness [ Time Frame: For the duration of the study, up to 15 months ]
   The rate of AEs was the number of AEs over the number of infusions administered. At least possibly related AEs included possibly related AEs, probably related AEs, and related AEs.
3. Rate of Mild, Moderate, or Severe Local Reactions [ Time Frame: For the duration of the study, up to 15 months ]

   In addition to the standard MedDRA System Organ Class (SOC) AE assignments, the category of 'local reactions' was defined to provide the possibility for a combined analysis of local reactions and included AEs of injection site reaction, injection site bruising, infusion site scab, injection site cyst, injection site eczema, injection site irritation, injection site nodule, and injection site pain.

   Mild AE: Did not interfere with routine activities; Moderate AE: Interfered somewhat with routine activities; Severe AE: Impossible to perform routine activities.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 75 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female aged 2 to 75 years
• Subjects with primary humoral immunodeficiency, namely with a diagnosis of: CVID (Common Variable Immunodeficiency) as defined by PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies) or XLA (X-linked Agammaglobulinemia)
• Written informed consent

Exclusion Criteria:

• Newly diagnosed PID
• Evidence of an active serious infection at the time of screening (i.e., but not limited to: bacteremia/septicemia, pneumonia, fungal osteomyelitis)
• Malignancies of lymphoid cells such as lymphocytic leukemia, Non-Hodgkin's lymphoma and immunodeficiency with thymoma
• Known hyperprolinemia
• Hypoalbuminemia, protein-losing enteropathies, and any proteinuria
• Allergic reactions to immunoglobulins or other blood products
• Known antibodies to Immunoglobulin A (IgA)
• The subject is receiving steroids (oral and parenteral, daily ≥ 0.15 mg of prednisone equivalent/kg/day) or other systemic immunosuppressants
• Female who is pregnant, breast feeding or planning a pregnancy during the course of the study
• Participation in a study with an investigational product other than (IVIG) within 1 month prior to enrollment
• A positive result at screening on any of the following viral markers: Human Immunodeficiency Virus (HIV), Hepatitis C virus (HCV) and Hepatitis B virus (HBV)
• Aspartate aminotransferase (ASAT) or Alanine aminotransferase (ALAT) concentration > 2.5 times the upper normal limit (UNL)
• Creatinine concentration > 1.5 times the UNL
• Any condition that is likely to interfere with evaluation of the study drug or satisfactory conduct of the trial

Contacts and Locations

Locations

United States, California

Study Site

Los Angeles, California, United States, 90025

Study Site

Los Angeles, California, United States, 90027

United States, Colorado

Study Site

Centennial, Colorado, United States, 80112

United States, Florida

Study Site

North Palm Beach, Florida, United States, 33408

United States, Georgia

Study Site

Atlanta, Georgia, United States, 30322

United States, Indiana

Study Site

Fort Wayne, Indiana, United States, 46815

Study Site

Indianapolis, Indiana, United States, 46202

United States, Iowa

Study Site

Iowa City, Iowa, United States, 52242

United States, Missouri

Study Site

St.Louis, Missouri, United States, 63104-1095

United States, New Jersey

Study Site

Newark, New Jersey, United States, 07103

United States, New York

Study Site

New York, New York, United States, 10029

United States, Pennsylvania

Study Site

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Study Site

Dallas, Texas, United States, 75230

Sponsors and Collaborators

CSL Behring

Investigators

• Principal Investigator: Richard L. Wasserman, MD, PhD; Dallas Allergy Immunology and Medical City Children's Hospital,

More Information

Additional Information:

Related Info 

Publications of Results:

Hagan JB, Fasano MB, Spector S, Wasserman RL, Melamed I, Rojavin MA, Zenker O, Orange JS. Efficacy and safety of a new 20% immunoglobulin preparation for subcutaneous administration, IgPro20, in patients with primary immunodeficiency. J Clin Immunol. 2010 Sep;30(5):734-45. doi: 10.1007/s10875-010-9423-4. Epub 2010 May 8.

Wasserman RL, Melamed I, Nelson RP Jr, Knutsen AP, Fasano MB, Stein MR, Rojavin MA, Church JA. Pharmacokinetics of subcutaneous IgPro20 in patients with primary immunodeficiency. Clin Pharmacokinet. 2011 Jun;50(6):405-14. doi: 10.2165/11587030-000000000-00000.

• Responsible Party: CSL Behring
• ClinicalTrials.gov Identifier: NCT00419341
• Other Study ID Numbers: ZLB04_009CR; 1458 ( Other Identifier: CSL Behring )
• First Posted: January 8, 2007
• Results First Posted: January 25, 2013
• Last Update Posted: January 25, 2013
• Last Verified: December 2012

Keywords provided by CSL Behring:

Immune globulin subcutaneous; SCIG; Primary immunodeficiency; PID

Additional relevant MeSH terms:

Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Genetic Diseases, Inborn; Immune System Diseases; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; Immunologic Factors; Physiological Effects of Drugs