Primary Immune Deficiency
Conditions
Keywords
Immune globulin subcutaneous, SCIG, Primary immunodeficiency, PID
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).
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.
Interventions
BIOLOGICALHuman Normal Immunoglobulin for Subcutaneous Administration
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Clinically Documented Serious Bacterial Infections (SBIs) (MITT Population) | 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. |
| Area Under the Concentration-time Curve (AUC) of Total Serum Immunoglobulin G (IgG) | 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
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Clinically Documented SBIs (PPE Population) | 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. |
| Annualized Rate of Infection Episodes | 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. |
| Number of Infection Episodes (Serious and Non-serious) | Efficacy period: up to 12 months (week 13 to the completion visit) | Total number of infections for the specified analysis population |
| Annualized Rate of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections | 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. |
| Number of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections | 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 |
| Annualized Rate of Clinically Documented SBIs (ITT Population) | 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. |
| Total Serum IgG Trough Levels | 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. |
| Maximum Concentration (Cmax) of Total Serum IgG at Steady State | Week 28 ± 1 week of the treatment period | — |
| Tmax at Steady State | Week 28 ± 1 week of the treatment period | Timepoint of maximum concentration (Cmax) |
| Annualized Rate of Hospitalization Due to Infection | 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. |
| Number of Days of Hospitalization Due to Infections | 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 |
| Use of Antibiotics for Infection Prophylaxis and Treatment | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Minimum Concentration (Cmin) of Total Serum IgG at Steady State | Week 28 ± 1 week of the treatment period | — |
| Rate of Mild, Moderate, or Severe Local Reactions | 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. |
| Rate of All AEs by Relatedness and Seriousness | 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. |
Countries
United States
Participant flow
Recruitment details
A total of 12 centers in the United States enrolled subjects for this study.
Participants by arm
| Arm | Count |
|---|---|
| IgPro20 IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a SC infusion at weekly intervals. | 49 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Efficacy Period | Lost to Follow-up | 1 |
| Efficacy Period | Non-compliance | 1 |
| Efficacy Period | Protocol Violation | 1 |
| Efficacy Period | Termination of study site | 1 |
| Efficacy Period | Withdrawal by Subject | 6 |
| Wash in/Wash Out Period | Adverse Event | 2 |
| Wash in/Wash Out Period | Disqualifying laboratory results | 1 |
| Wash in/Wash Out Period | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | IgPro20 |
|---|---|
| Age Continuous | 34.4 years STANDARD_DEVIATION 20.09 |
| Age, Customized 12 to < 16 years | 7 participants |
| Age, Customized 16 to < 65 years | 33 participants |
| Age, Customized 2 to < 12 years | 3 participants |
| Age, Customized ≥ 65 years | 6 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants |
| Race/Ethnicity, Customized White | 46 participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 22 Participants |
| Type of Primary Immunodeficiency Common variable immunodeficiency (CVID) | 46 participants 21.24 |
| Type of Primary Immunodeficiency X-linked agammaglobulinemia (XLA) | 3 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 49 / 49 |
| serious Total, serious adverse events | 7 / 49 |
Outcome results
Primary
Annualized Rate of Clinically Documented Serious Bacterial Infections (SBIs) (MITT Population)
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.
Time frame: Efficacy period: up to 12 months (week 13 to the completion visit)
Population: The modified intention-to-treat (MITT) population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 13) who had the disease under study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Annualized Rate of Clinically Documented Serious Bacterial Infections (SBIs) (MITT Population) | 0.00 SBIs per subject year |
Primary
Area Under the Concentration-time Curve (AUC) of Total Serum Immunoglobulin G (IgG)
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 \[NCT00322556\]).
Time frame: Measured during a single dosing interval after at least 12 weeks of stable subcutaneous (SC) dosing with IgPro20 treatment
Population: The Per Protocol Pharmacokinetic (PPK) population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IgPro20 | Area Under the Concentration-time Curve (AUC) of Total Serum Immunoglobulin G (IgG) | 105.6 days*g/L | Standard Deviation 31.56 |
| IVIG (Privigen; Previous Study) | Area Under the Concentration-time Curve (AUC) of Total Serum Immunoglobulin G (IgG) | 103.2 days*g/L | Standard Deviation 20 |
Comparison: Individual sAUC values (standardized to a 7-day period) of the IV and adjusted SC sampling periods in each individual subject were log transformed and a parametric 2-sided 90% confidence interval (CI) for the mean of the individual differences was obtained. Back-transformation of the mean and its CI produced the geometric mean ratio (GMR) and its respective 90% CI.90% CI: [0.951, 1.055]t-test, 2 sided
Secondary
Annualized Rate of Clinically Documented SBIs (ITT Population)
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.
Time frame: For the duration of the study, up to 15 months
Population: The Intention To Treat (ITT) population included all subjects who were treated with IgPro20 during any study period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Annualized Rate of Clinically Documented SBIs (ITT Population) | 0.00 SBIs per subject year |
Secondary
Annualized Rate of Clinically Documented SBIs (PPE Population)
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.
Time frame: Efficacy period: up to 12 months (week 13 to the completion visit)
Population: The Per Protocol Efficacy (PPE) population included all subjects who completed the 12-month efficacy period according to the protocol-defined requirements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Annualized Rate of Clinically Documented SBIs (PPE Population) | 0.00 SBIs per subject year |
Secondary
Annualized Rate of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections
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.
Time frame: Efficacy period: up to 12 months (week 13 to the completion visit)
Population: The modified intention-to-treat (MITT) population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 13) who had the disease under study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Annualized Rate of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections | 2.06 days per subject year |
Secondary
Annualized Rate of Hospitalization Due to Infection
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.
Time frame: Efficacy period: up to 12 months (week 13 to the completion visit)
Population: The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Annualized Rate of Hospitalization Due to Infection | 0.20 days per subject year |
Secondary
Annualized Rate of Infection Episodes
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.
Time frame: Efficacy period: up to 12 months (week 13 to completion visit)
Population: The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 13) who had the disease under study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Annualized Rate of Infection Episodes | 2.76 infection episodes per subject year |
Secondary
Maximum Concentration (Cmax) of Total Serum IgG at Steady State
Time frame: Week 28 ± 1 week of the treatment period
Population: The PPK population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IgPro20 | Maximum Concentration (Cmax) of Total Serum IgG at Steady State | 16.16 g/L | Standard Deviation 4.93 |
Secondary
Number of Days of Hospitalization Due to Infections
Total number of days of hospitalization due to infections for the specified analysis population
Time frame: Efficacy period: up to 12 months (week 13 to the completion visit)
Population: The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Number of Days of Hospitalization Due to Infections | 7 days |
Secondary
Number of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections
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
Time frame: Efficacy period: up to 12 months (week 13 to the completion visit)
Population: The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Number of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections | 71 days |
Secondary
Number of Infection Episodes (Serious and Non-serious)
Total number of infections for the specified analysis population
Time frame: Efficacy period: up to 12 months (week 13 to the completion visit)
Population: The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Number of Infection Episodes (Serious and Non-serious) | 96 infections |
Secondary
Tmax at Steady State
Timepoint of maximum concentration (Cmax)
Time frame: Week 28 ± 1 week of the treatment period
Population: The PPK population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| IgPro20 | Tmax at Steady State | 3.118 days | Full Range 1.7729 |
Secondary
Total Serum IgG Trough Levels
The IgG trough values per subject were aggregated to a median value, and then median values across subjects were summarized using descriptive statistics.
Time frame: Every 4 weeks, throughout the 12-month efficacy period
Population: The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IgPro20 | Total Serum IgG Trough Levels | 12.53 g/L | Standard Deviation 3.21 |
Secondary
Use of Antibiotics for Infection Prophylaxis and Treatment
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.
Time frame: Efficacy period: up to 12 months (week 13 to the completion visit)
Population: The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro20 | Use of Antibiotics for Infection Prophylaxis and Treatment | 48.52 days per subject year |
Other Pre-specified
Minimum Concentration (Cmin) of Total Serum IgG at Steady State
Time frame: Week 28 ± 1 week of the treatment period
Population: The PPK population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IgPro20 | Minimum Concentration (Cmin) of Total Serum IgG at Steady State | 13.70 g/L | Standard Deviation 4.39 |
Other Pre-specified
Rate of All AEs by Relatedness and Seriousness
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.
Time frame: For the duration of the study, up to 15 months
Population: The ITT population included all subjects who were treated with IgPro20 during any study period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IgPro20 | Rate of All AEs by Relatedness and Seriousness | All | 0.773 AEs per infusion |
| IgPro20 | Rate of All AEs by Relatedness and Seriousness | At least possibly related | 0.634 AEs per infusion |
| IgPro20 | Rate of All AEs by Relatedness and Seriousness | Serious | 0.004 AEs per infusion |
| IgPro20 | Rate of All AEs by Relatedness and Seriousness | At least possibly related and serious | 0 AEs per infusion |
Other Pre-specified
Rate of Mild, Moderate, or Severe Local Reactions
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.
Time frame: For the duration of the study, up to 15 months
Population: The ITT population included all subjects who were treated with IgPro20 during any study period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IgPro20 | Rate of Mild, Moderate, or Severe Local Reactions | All | 0.592 local reactions per infusion |
| IgPro20 | Rate of Mild, Moderate, or Severe Local Reactions | Mild | 0.553 local reactions per infusion |
| IgPro20 | Rate of Mild, Moderate, or Severe Local Reactions | Moderate | 0.038 local reactions per infusion |
| IgPro20 | Rate of Mild, Moderate, or Severe Local Reactions | Severe | 0.002 local reactions per infusion |