Tolerability and Safety of IGI, 10% With rHuPH20 in PIDD

Study Overview
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Brief Summary
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The purpose of the study is to acquire additional data on safety and tolerability of recombinant human hyaluronidase (rHuPH20) facilitated subcutaneous treatment of Immune Globulin Infusion (Human), 10% (IGI, 10%) and to assess the mode of product administration. Following a discussion with the FDA at the end of July 2012, all participants still active in the study stopped treatment with rHuPH20 to assure safety of the participants participating in the study and went into a safety follow-up. During this safety follow-up period, participants underwent treatment with the licensed product IGI, 10% (Gammagard Liquid). The intravenous or subcutaneous administration route was at the discretion of the participant and the investigator.

Official Title
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Tolerability, Safety and Administration Mode Evaluation of Recombinant Human Hyaluronidase (rHuPH20) Facilitated Subcutaneous Treatment With Immune Globulin Infusion (Human), 10% in Subjects With Primary Immunodeficiency Diseases (PIDD)

Conditions
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Primary Immunodeficiency Diseases (PID)

Intervention / Treatment
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* Biological: Immune Globulin Infusion (Human), 10%
* Biological: Recombinant human hyaluronidase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have a documented diagnosis of a form of primary humoral immunodeficiency involving a defect in antibody formation and requiring gammaglobulin replacement, as defined according to the IUIS Scientific Committee 2009 and by diagnostic criteria according to Conley et al. The diagnosis must be reviewed by the Medical Director prior to enrollment. Subject is 2 years or older at the time of screening. Written informed consent is obtained from either the subject or the subject's legally authorized representative prior to any study-related procedures and study product administration. Subject has been receiving a consistent dose of immunoglobulin G (IgG) with a non-Baxter product (Gammunex administered IV, Hizentra, or Privigen), administered in compliance with the respective product information, for a period of at least 3 months prior to screening. The average minimum pre-study dose over that interval was equivalent to 300 mg/kg BW/4 weeks and a maximum dose equivalent to 600 mg/kg BW/4 weeks at a dosing frequency as follows: For IV treatment prior to the study: at mean intervals of 3 or 4 weeks (+/- 3 days) or For SC treatment prior to the study: at mean intervals of approximately 1 or 2 weeks (+/- 2 days). Subject has a serum trough level of IgG > 5 g/L at screening. Subject has not had a serious bacterial infection within the 3 months prior to screening. If female of childbearing potential, subject presents with a negative pregnancy test and agrees to employ adequate birth control measures for the duration of the study. Subject is willing and able to comply with the requirements of the protocol. Exclusion Criteria: Subject has a known history of or is positive at screening for one or more of the following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1/2. Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent): Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) > 2.5 times the upper limit of normal for the testing laboratory Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] <= 500/mm3). Subject has creatinine clearance (CLcr) value that is <60% of normal for age and gender either measured, or calculated according to a gender-specific formula provided in the study protocol. Subject has been diagnosed with or has a malignancy (other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix), unless the disease-free period prior to screening exceeds 5 years Subject is receiving anti-coagulation therapy or has a history of thrombotic episodes (including deep vein thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism) within 12 months prior to screening or a history of thrombophilia. Subject has abnormal protein loss (protein losing enteropathy, nephrotic syndrome). Subject has anemia that would preclude phlebotomy for laboratory studies, according to standard practice at the site. Subject has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, and/or Immune Serum Globulin (ISG) infusions. Subject has immunoglobulin A (IgA) deficiency (IgA less than 0.07g/L) and known anti IgA antibodies. Subject has a known allergy to hyaluronidase. Subject is on preventative (prophylactic) systemic antibacterial antibiotics at doses sufficient to treat or prevent bacterial infections, and cannot stop these antibiotics at the time of screening. Subject has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening. Subject has a bleeding disorder or a platelet count less than 20,000/μL, or who, in the opinion of the investigator, would be at significant risk of increased bleeding or bruising as a result of SC therapy. Subject has total protein > 9 g/dL or myeloma, or macroglobulinemia (IgM) or paraproteinemia. Women of childbearing potential meeting any one of the following criteria: Subject presents with a positive pregnancy test Subject is breast feeding Subject intends to begin nursing during the course of the study Subject does not agree to employ adequate birth-control measures (e.g. intrauterine device, diaphragm or condom [for male partner] with spermicidal jelly or foam, or birth control pills/patches) throughout the course of the study. Subject has participated in another clinical study and has been exposed to an investigational product (IP) or device within 30 days prior to study enrollment (exception: treatment with immunoglobulin pre-study). Subject is scheduled to participate in another (non-Baxter) clinical study involving an IP or device during the course of the study. Subject has severe dermatitis that would preclude adequate sites for safe product administration.

Ages Eligible for Study
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Minimum Age: 2 Years

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epoch 1 and Epoch 2<br>In Study Epoch 1 PIDD patients that are already on intravenous treatment or subcutaneous treatment will be enrolled and treated with IGI, 10% and rHuPH20 subcutaneously, with a short dose/interval ramp-up (Epoch 1) consisting of one 1-week dose and interval and one 2-week dose and interval. The ramp-up (Epoch 1) is followed by Epoch 2 which consists of approximately 6 months (24 weeks) of IGI, 10% and rHuPH20 treatment. For subjects pretreated intravenously (IV), this treatment will occur every 3 or 4 weeks (at a 3-week or 4-week dose, respectively), depending on the subject´s previous IV dosing schedule. For subjects pretreated subcutaneously (SC), treatment will also occur every 3 or 4 weeks (at a 3-week or 4-week dose, respectively), at the discretion of the investigator and subject. | Biological: Immune Globulin Infusion (Human), 10%<br>* Subcutaneous administration will be used in Study Epochs 1 and 2.<br>* Other names: 10%;Biological: Recombinant human hyaluronidase<br>* rHuPH20 will be administered subcutaneously (SC) immediately before each SC IGI, 10% infusion, through the same needle, at a rate of 1 to 2 mL/min.<br>* Other names: rHuPH20;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Related Systemic Adverse Events (Excluding Infections) |  | 7 months (per subject) | 
| Rate of Related Systemic Adverse Events (Excluding Infections) Per Infusion | A point estimate and 95% confidence interval for the rate of related systemic adverse events per infusion was derived using a Poisson model. | 7 months (per subject) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Who Achieve a Treatment Interval of 3 or 4 Weeks in Epoch 2 |  | 6 months (per subject) | 
| Proportion of Subjects Who Maintain a Treatment Interval of 3 or 4 Weeks in Epoch 2 for 24 Weeks |  | 6 months (per subject) | 
| Number of Related Local Adverse Events (Excluding Infections) |  | 7 months (per subject) | 
| Rate of Related Local Adverse Events (Excluding Infections) Per Infusion | A point estimate and 95% confidence interval for the rate of related local adverse events per infusion was derived using a Poisson model. | 7 months (per subject) | 
| Number of All Related Adverse Events (Excluding Infections) |  | 7 months (per subject) | 
| Rate of All Adverse Events (Excluding Infections) Per Infusion | A point estimate and 95% confidence interval for the rate of adverse events per infusion was derived using a Poisson model. | 7 months (per subject) | 
| Number of Subjects Who Develop Neutralizing Antibodies to rHuPH20 |  | 7 months (per subject) | 
| Trough Levels of Immunoglobulin G (IgG) | IgG trough levels at the beginning of Study Epoch 1 (previous immunoglobulin treatment) and at the end of Study Epoch 2 were analyzed. | 7 months (per subject) | 
| Number of Infusions Per Month in Epoch 1 and Epoch 2 | Non-parametric descriptive statistics (median, range) are provided. | 7 months (per subject) | 
| Number of Infusion Sites (Needle Sticks) Per Month in Epoch 1 and Epoch 2 | Non-parametric descriptive statistics (median, range) are provided. | 7 months (per subject) | 
| Duration of Infusion in Epoch 1 and Epoch 2 | Non-parametric descriptive statistics (median, range) are provided. | 7 months (per subject) | 
| Maximum Infusion Rate in Epoch 1 and Epoch 2 | Non-parametric descriptive statistics (median, range) are provided. | 7 months (per subject) | 
| Number of Weeks to Reach Final 3 or 4-week Dose Interval | Non-parametric descriptive statistics (median, range) are provided. | 7 months (per subject) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PIDD