Primary Immunodeficiency Diseases (PID)
Conditions
Keywords
PIDD
Brief summary
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.
Interventions
BIOLOGICALImmune Globulin Infusion (Human), 10%
Subcutaneous administration will be used in Study Epochs 1 and 2.
BIOLOGICALRecombinant human hyaluronidase
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.
Sponsors
Baxalta now part of Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Related Systemic Adverse Events (Excluding Infections) | 7 months (per subject) | — |
| Rate of Related Systemic Adverse Events (Excluding Infections) Per Infusion | 7 months (per subject) | A point estimate and 95% confidence interval for the rate of related systemic adverse events per infusion was derived using a Poisson model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Related Local Adverse Events (Excluding Infections) | 7 months (per subject) | — |
| Rate of Related Local Adverse Events (Excluding Infections) Per Infusion | 7 months (per subject) | A point estimate and 95% confidence interval for the rate of related local adverse events per infusion was derived using a Poisson model. |
| Number of All Related Adverse Events (Excluding Infections) | 7 months (per subject) | — |
| Rate of All Adverse Events (Excluding Infections) Per Infusion | 7 months (per subject) | A point estimate and 95% confidence interval for the rate of adverse events per infusion was derived using a Poisson model. |
| Number of Subjects Who Develop Neutralizing Antibodies to rHuPH20 | 7 months (per subject) | — |
| Proportion of Subjects Who Achieve a Treatment Interval of 3 or 4 Weeks in Epoch 2 | 6 months (per subject) | — |
| Number of Infusions Per Month in Epoch 1 and Epoch 2 | 7 months (per subject) | Non-parametric descriptive statistics (median, range) are provided. |
| Number of Infusion Sites (Needle Sticks) Per Month in Epoch 1 and Epoch 2 | 7 months (per subject) | Non-parametric descriptive statistics (median, range) are provided. |
| Duration of Infusion in Epoch 1 and Epoch 2 | 7 months (per subject) | Non-parametric descriptive statistics (median, range) are provided. |
| Maximum Infusion Rate in Epoch 1 and Epoch 2 | 7 months (per subject) | Non-parametric descriptive statistics (median, range) are provided. |
| Number of Weeks to Reach Final 3 or 4-week Dose Interval | 7 months (per subject) | Non-parametric descriptive statistics (median, range) are provided. |
| Trough Levels of Immunoglobulin G (IgG) | 7 months (per subject) | IgG trough levels at the beginning of Study Epoch 1 (previous immunoglobulin treatment) and at the end of Study Epoch 2 were analyzed. |
| Proportion of Subjects Who Maintain a Treatment Interval of 3 or 4 Weeks in Epoch 2 for 24 Weeks | 6 months (per subject) | — |
Countries
United States
Participant flow
Recruitment details
Enrollment was conducted at 16 study sites in the US.
Pre-assignment details
Of 54 subjects screened for the study, 37 started treatment. Of the 17 subjects who discontinued the study before treatment, 10 were screen failures, 5 withdrew consent, and for 2 subjects enrollment ended due to other reasons.
Participants by arm
| Arm | Count |
|---|---|
| Subcutaneous Treatment With IGI, 10% and rHuPH20 This analysis set comprises all subjects exposed to study drug in Epoch 1 and Epoch 2. In Epoch 1, PIDD patients that were already on intravenous (IV) or subcutaneous (SC) treatment were treated with IGI, 10% and rHuPH20 subcutaneously, with one 1-week dose and interval and one 2-week dose and interval. Epoch 2 was to consist of approx. 6 months (24 weeks) of IGI, 10% and rHuPH20 treatment. For subjects pretreated IV, this treatment was to 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 SC, treatment was also to occur every 3 or 4 weeks (at a 3-week or 4-week dose, respectively), at the discretion of the investigator and subject. However, treatment with rHuPH20 was stopped as of August 2012 following a discussion with the FDA, and subjects still active in Epoch 2 were switched to a safety follow-up (IGI, 10% by IV or SC route). | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Trial (Incl. Safety Follow-up) | Adverse Event in Epoch 2 | 3 |
| Overall Trial (Incl. Safety Follow-up) | Withdrawal by Subject in Epoch 1 | 1 |
| Overall Trial (Incl. Safety Follow-up) | Withdrawal by Subject in Epoch 2 | 6 |
| Overall Trial (Incl. Safety Follow-up) | Withdrawal During Safety-Follow-up | 2 |
| Period 1: Epoch 1 (Ramp-up) | Withdrawal by Subject | 1 |
| Period 2: Epoch 2 | Adverse Event | 3 |
| Period 2: Epoch 2 | Switch to safety follow-up | 26 |
| Period 2: Epoch 2 | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Subcutaneous Treatment With IGI, 10% and rHuPH20 |
|---|---|
| Age, Categorical <=18 years | 12 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 33.0 Years |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 37 | 10 / 26 |
| serious Total, serious adverse events | 0 / 37 | 1 / 26 |
Outcome results
Primary
Number of Related Systemic Adverse Events (Excluding Infections)
Time frame: 7 months (per subject)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Analysis Set (n=37) | Number of Related Systemic Adverse Events (Excluding Infections) | 59 adverse events |
Primary
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.
Time frame: 7 months (per subject)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Rate of Related Systemic Adverse Events (Excluding Infections) Per Infusion | Epoch 1 | 0.250 adverse events |
| Safety Analysis Set (n=37) | Rate of Related Systemic Adverse Events (Excluding Infections) Per Infusion | Epoch 2 | 0.377 adverse events |
| Safety Analysis Set (n=37) | Rate of Related Systemic Adverse Events (Excluding Infections) Per Infusion | Epoch 1+2 | 0.324 adverse events |
| Epoch 2 Data Set (n=36) | Rate of Related Systemic Adverse Events (Excluding Infections) Per Infusion | Epoch 1 | 0.253 adverse events |
| Epoch 2 Data Set (n=36) | Rate of Related Systemic Adverse Events (Excluding Infections) Per Infusion | Epoch 2 | 0.377 adverse events |
| Epoch 2 Data Set (n=36) | Rate of Related Systemic Adverse Events (Excluding Infections) Per Infusion | Epoch 1+2 | 0.326 adverse events |
Secondary
Duration of Infusion in Epoch 1 and Epoch 2
Non-parametric descriptive statistics (median, range) are provided.
Time frame: 7 months (per subject)
Population: The number of participants analyzed for Epoch 1 is 37, as 37 participants were treated with study drug in Epoch 1. The number of participants analyzed for Epoch 2 is 36, as 36 participants were treated with study drug in Epoch 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Duration of Infusion in Epoch 1 and Epoch 2 | Epoch 1 | 1.23 hours |
| Safety Analysis Set (n=37) | Duration of Infusion in Epoch 1 and Epoch 2 | Epoch 2 | 1.67 hours |
Secondary
Maximum Infusion Rate in Epoch 1 and Epoch 2
Non-parametric descriptive statistics (median, range) are provided.
Time frame: 7 months (per subject)
Population: The number of participants analyzed for Epoch 1 is 37, as 37 participants were treated with study drug in Epoch 1. The number of participants analyzed for Epoch 2 is 36, as 36 participants were treated with study drug in Epoch 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Maximum Infusion Rate in Epoch 1 and Epoch 2 | Epoch 1 | 240.0 mL/h |
| Safety Analysis Set (n=37) | Maximum Infusion Rate in Epoch 1 and Epoch 2 | Epoch 2 | 300.0 mL/h |
Secondary
Number of All Related Adverse Events (Excluding Infections)
Time frame: 7 months (per subject)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Analysis Set (n=37) | Number of All Related Adverse Events (Excluding Infections) | 212 adverse events |
Secondary
Number of Infusion Sites (Needle Sticks) Per Month in Epoch 1 and Epoch 2
Non-parametric descriptive statistics (median, range) are provided.
Time frame: 7 months (per subject)
Population: The number of participants analyzed for Epoch 1 is 37, as 37 participants were treated with study drug in Epoch 1. The number of participants analyzed for Epoch 2 is 36, as 36 participants were treated with study drug in Epoch 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Number of Infusion Sites (Needle Sticks) Per Month in Epoch 1 and Epoch 2 | Epoch 2 | 1.12 infusion sites (needle sticks) |
| Safety Analysis Set (n=37) | Number of Infusion Sites (Needle Sticks) Per Month in Epoch 1 and Epoch 2 | Epoch 1 | 2.90 infusion sites (needle sticks) |
Secondary
Number of Infusions Per Month in Epoch 1 and Epoch 2
Non-parametric descriptive statistics (median, range) are provided.
Time frame: 7 months (per subject)
Population: The number of participants analyzed for Epoch 1 is 37, as 37 participants were treated with study drug in Epoch 1. The number of participants analyzed for Epoch 2 is 36, as 36 participants were treated with study drug in Epoch 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Number of Infusions Per Month in Epoch 1 and Epoch 2 | Epoch 1 | 2.90 infusions |
| Safety Analysis Set (n=37) | Number of Infusions Per Month in Epoch 1 and Epoch 2 | Epoch 2 | 1.09 infusions |
Secondary
Number of Related Local Adverse Events (Excluding Infections)
Time frame: 7 months (per subject)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Analysis Set (n=37) | Number of Related Local Adverse Events (Excluding Infections) | 153 adverse events |
Secondary
Number of Subjects Who Develop Neutralizing Antibodies to rHuPH20
Time frame: 7 months (per subject)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Analysis Set (n=37) | Number of Subjects Who Develop Neutralizing Antibodies to rHuPH20 | 0 subjects |
Secondary
Number of Weeks to Reach Final 3 or 4-week Dose Interval
Non-parametric descriptive statistics (median, range) are provided.
Time frame: 7 months (per subject)
Population: Of 36 participants treated with study drug in Epoch 2, 6 reached a final dose interval of 3 weeks and 30 reached a final dose interval of 4 weeks.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Number of Weeks to Reach Final 3 or 4-week Dose Interval | 3-week dose interval | 3.0 weeks |
| Safety Analysis Set (n=37) | Number of Weeks to Reach Final 3 or 4-week Dose Interval | 4-week dose interval | 3.0 weeks |
Secondary
Proportion of Subjects Who Achieve a Treatment Interval of 3 or 4 Weeks in Epoch 2
Time frame: 6 months (per subject)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Proportion of Subjects Who Achieve a Treatment Interval of 3 or 4 Weeks in Epoch 2 | 3 or 4-week treatment interval | 36 subjects |
| Safety Analysis Set (n=37) | Proportion of Subjects Who Achieve a Treatment Interval of 3 or 4 Weeks in Epoch 2 | 3-week treatment interval | 6 subjects |
| Safety Analysis Set (n=37) | Proportion of Subjects Who Achieve a Treatment Interval of 3 or 4 Weeks in Epoch 2 | 4-week treatment interval | 30 subjects |
Secondary
Proportion of Subjects Who Maintain a Treatment Interval of 3 or 4 Weeks in Epoch 2 for 24 Weeks
Time frame: 6 months (per subject)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Analysis Set (n=37) | Proportion of Subjects Who Maintain a Treatment Interval of 3 or 4 Weeks in Epoch 2 for 24 Weeks | 1 subjects |
Secondary
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.
Time frame: 7 months (per subject)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Rate of All Adverse Events (Excluding Infections) Per Infusion | Epoch 1+2 | 1.643 adverse events |
| Safety Analysis Set (n=37) | Rate of All Adverse Events (Excluding Infections) Per Infusion | Epoch 1 | 1.645 adverse events |
| Safety Analysis Set (n=37) | Rate of All Adverse Events (Excluding Infections) Per Infusion | Epoch 2 | 1.642 adverse events |
| Epoch 2 Data Set (n=36) | Rate of All Adverse Events (Excluding Infections) Per Infusion | Epoch 1+2 | 1.646 adverse events |
| Epoch 2 Data Set (n=36) | Rate of All Adverse Events (Excluding Infections) Per Infusion | Epoch 2 | 1.642 adverse events |
| Epoch 2 Data Set (n=36) | Rate of All Adverse Events (Excluding Infections) Per Infusion | Epoch 1 | 1.653 adverse events |
Secondary
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.
Time frame: 7 months (per subject)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Rate of Related Local Adverse Events (Excluding Infections) Per Infusion | Epoch 1 | 0.882 adverse events |
| Safety Analysis Set (n=37) | Rate of Related Local Adverse Events (Excluding Infections) Per Infusion | Epoch 2 | 0.811 adverse events |
| Safety Analysis Set (n=37) | Rate of Related Local Adverse Events (Excluding Infections) Per Infusion | Epoch 1+2 | 0.841 adverse events |
| Epoch 2 Data Set (n=36) | Rate of Related Local Adverse Events (Excluding Infections) Per Infusion | Epoch 1 | 0.880 adverse events |
| Epoch 2 Data Set (n=36) | Rate of Related Local Adverse Events (Excluding Infections) Per Infusion | Epoch 2 | 0.811 adverse events |
| Epoch 2 Data Set (n=36) | Rate of Related Local Adverse Events (Excluding Infections) Per Infusion | Epoch 1+2 | 0.840 adverse events |
Secondary
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.
Time frame: 7 months (per subject)
Population: At screening, data (ie, IgG trough levels) were available for analysis from 36 participants. At the end of Epoch 2, data were available for analysis from only 33 participants.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Safety Analysis Set (n=37) | Trough Levels of Immunoglobulin G (IgG) | At screening | 10.53 g/L |
| Safety Analysis Set (n=37) | Trough Levels of Immunoglobulin G (IgG) | At end of Epoch 2 | 9.21 g/L |