Agammaglobulinemia, Common Variable Immunodeficiency, IgG Deficiency
Conditions
Keywords
Immunoglobulin Intravenous, Agammaglobulinemia, Hypogammaglobulinemia, Common variable immunodeficiency, Immunoglobulin G, Children
Brief summary
The objectives of this trial are the assessment of safety and efficacy of IgPro10 in patients with PID, and the assessment of tolerability of high infusion rates. To demonstrate safety, the number of infusions temporally associated with AEs, the rate, severity and relationship of all AEs and the vital sign changes during each infusion will be evaluated.
Interventions
Liquid formulation; treatment schedule every 3 or 4 weeks using an individualized regimen with a dose of 0.2 - 0.8 g IgG per kg bw
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 71 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Patients with CVID (Common Variable Immunodeficiency) or XLA (X-linked agammaglobulinemia) who: Participated in the Phase III clinical study with intravenous IgPro10 (study number ZLB03\_002CR) at 3- or 4- weekly intervals for 12 months (referred to as 'old' subjects) OR Were ≥ 6 years of age, were on other stable intravenous immunoglobulin therapy (200-800 mg IgG per kg body weight) at 3- or 4-week intervals for at least 6 months, AND were interested in participating in the Phase III clinical study with subcutaneous IgPro20 (study number ZLB04\_009CR) (referred to as 'new' subjects) Written informed consent Key
Exclusion criteria
Diagnosis of epilepsia Insulin dependent diabetes Administration of steroids (daily ≥ 0.15 mg prednisone equivalent/kg/day) or other immunosuppressive drugs History of cardiac insufficiency (NYHA III/IV), cardiomyopathy, congestive heart failure, severe hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Infusions With One or More Temporally-associated Adverse Events (AEs). | During each infusion, and within 48 or 72 hours after the end of each infusion. | AEs were considered temporally-associated AEs if they occurred during the infusion or in the period from the start of the infusion until either 48 or 72 hours after the end of the infusion. |
| Influence of Infusion Rate on Temporally-Associated AEs | Within 72 hours after each infusion | The total and most frequent (1% or more) number of infusions for which subjects experienced temporally-associated AEs occurring within 72 hours of infusion, by infusion rate (≤ 4 mg/kg/min, ≤ 8 mg/kg/min, and \> 8 and ≤ 12 mg/kg/min). AEs were considered to be temporally-associated AEs if they occurred in the period from the start of the infusion until 72 hours after the end of the infusion. |
| Rate of AEs by Severity and Relationship | For the duration of the study, up to approximately 29 months | The AE rate was the number of AEs over the number of infusions administered. Mild AEs: Did not interfere with daily activities; Moderate AEs: Interfered with routine daily activities; Severe AEs: Impossible to perform routine daily activities. At least possibly related AEs included possibly related AEs, probably related AEs, and related AEs. |
| Number of Subjects With Clinically Significant Changes in Vital Signs. | Before, during, and after each infusion. | Vital signs included heart rate, systolic blood pressure, diastolic blood pressure, and body temperature. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Acute Serious Bacterial Infections. | For the duration of the study, up to approximately 29 months | The annualized rate was based on the total number of infections and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days. Acute serious bacterial infections included pneumonia, bacteremia / septicemia, osteomyelitis / septic arthritis, bacterial meningitis, and visceral abscess. |
| Trough Levels of Total Immunoglobulin (IgG) Serum Concentrations. | Prior to each infusion; every 3 or 4 weeks depending upon the dosing schedule. | Mean IgG trough concentration. For this analysis, each subject's values were first aggregated to their median and the median values were then analyzed. |
| Number of Days Out of Work / School / Kindergarten / Day Care or Inability to Perform Normal Activities Due to Illness. | For the duration of the study, up to approximately 29 months. | — |
| Number of Days of Hospitalization. | For the duration of the study, up to approximately 29 months | — |
| Annualized Rate of Any Infection. | For the duration of the study, up to approximately 29 months. | The annualized rate was based on the total number of infections and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days. Infections were classified as all AEs with the system organ class infections and infestations and AEs with the preferred term conjunctivitis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IgPro10 A 10% liquid formulation of human immunoglobulin G (stabilized with 250 millimole per liter of L-proline) administered as an intravenous infusion, every 3 or 4 weeks for the duration of the study. | 55 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Other Reason | 7 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | IgPro10 |
|---|---|
| Age Continuous | 30 years STANDARD_DEVIATION 21 |
| Age, Customized 12 to < 16 years | 8 participants |
| Age, Customized 16 to < 65 years | 30 participants |
| Age, Customized 3 to < 12 years | 13 participants |
| Age, Customized >= 65 years | 4 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 48 / 55 |
| serious Total, serious adverse events | 11 / 55 |
Outcome results
Primary
Influence of Infusion Rate on Temporally-Associated AEs
The total and most frequent (1% or more) number of infusions for which subjects experienced temporally-associated AEs occurring within 72 hours of infusion, by infusion rate (≤ 4 mg/kg/min, ≤ 8 mg/kg/min, and \> 8 and ≤ 12 mg/kg/min). AEs were considered to be temporally-associated AEs if they occurred in the period from the start of the infusion until 72 hours after the end of the infusion.
Time frame: Within 72 hours after each infusion
Population: 'New subjects' could receive IgPro10 at up to 4 mg/kg/min. 'Old' subjects (ie, those treated with the study drug who participated in a preceding, pivotal, Phase III clinical study with intravenous IgPro10 \[study number ZLB03\_002CR, NCT00168025\]), could receive IgPro10 at up to 12 mg/kg/min at the discretion of the Investigator.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Chills | 0 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Nausea | 0 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Anaemia | 1 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Fatigue | 3 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Headache | 10 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Pain | 0 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Eczema | 1 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Constipation | 2 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Influenza like illness | 3 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Back pain | 0 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Myalgia | 1 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Pharyngolaryngeal pain | 1 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Night sweats | 1 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | All temporally-associated AEs | 23 Infusions |
| IgPro10 | Influence of Infusion Rate on Temporally-Associated AEs | Pyrexia | 0 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Myalgia | 0 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Constipation | 0 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Nausea | 8 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Pain | 6 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Chills | 7 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | All temporally-associated AEs | 153 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Anaemia | 0 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Back pain | 8 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Fatigue | 0 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Influenza like illness | 1 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Pharyngolaryngeal pain | 1 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Night sweats | 0 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Pyrexia | 9 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Eczema | 0 Infusions |
| IgPro10 (≤ 8 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Headache | 54 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Eczema | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | All temporally-associated AEs | 30 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Nausea | 2 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Back pain | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Chills | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Anaemia | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Constipation | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Influenza like illness | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Myalgia | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Night sweats | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Pyrexia | 1 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Pain | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Fatigue | 0 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Pharyngolaryngeal pain | 2 Infusions |
| IgPro10 (> 8 to ≤ 12 mg/kg/Min) | Influence of Infusion Rate on Temporally-Associated AEs | Headache | 2 Infusions |
Primary
Number of Subjects With Clinically Significant Changes in Vital Signs.
Vital signs included heart rate, systolic blood pressure, diastolic blood pressure, and body temperature.
Time frame: Before, during, and after each infusion.
Population: The Safety Data Set (SDS) comprised all subjects treated with the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro10 | Number of Subjects With Clinically Significant Changes in Vital Signs. | 0 Participants |
Primary
Rate of AEs by Severity and Relationship
The AE rate was the number of AEs over the number of infusions administered. Mild AEs: Did not interfere with daily activities; Moderate AEs: Interfered with routine daily activities; Severe AEs: Impossible to perform routine daily activities. 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 approximately 29 months
Population: The SDS comprised all subjects treated with the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IgPro10 | Rate of AEs by Severity and Relationship | All mild AEs | 0.467 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | All moderate AEs | 0.280 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | All severe AEs | 0.058 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | Unrelated AEs | 0.610 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | Probably related AEs | 0.048 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | Related AEs | 0.060 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | At least possibly related mild AEs | 0.121 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | At least possibly related moderate AEs | 0.062 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | At least possibly related severe AEs | 0.013 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | Unrelated mild AEs | 0.346 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | Unrelated moderate AEs | 0.218 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | Unrelated severe AEs | 0.045 AEs per infusion |
| IgPro10 | Rate of AEs by Severity and Relationship | Possibly related AEs | 0.088 AEs per infusion |
Primary
The Proportion of Infusions With One or More Temporally-associated Adverse Events (AEs).
AEs were considered temporally-associated AEs if they occurred during the infusion or in the period from the start of the infusion until either 48 or 72 hours after the end of the infusion.
Time frame: During each infusion, and within 48 or 72 hours after the end of each infusion.
Population: The Safety Data Set (SDS) comprised all subjects treated with the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IgPro10 | The Proportion of Infusions With One or More Temporally-associated Adverse Events (AEs). | During infusion | 0.073 Proportion of infusions |
| IgPro10 | The Proportion of Infusions With One or More Temporally-associated Adverse Events (AEs). | Within 48 hours after infusion | 0.141 Proportion of infusions |
| IgPro10 | The Proportion of Infusions With One or More Temporally-associated Adverse Events (AEs). | Within 72 hours after infusion | 0.150 Proportion of infusions |
Secondary
Annualized Rate of Acute Serious Bacterial Infections.
The annualized rate was based on the total number of infections and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days. Acute serious bacterial infections included pneumonia, bacteremia / septicemia, osteomyelitis / septic arthritis, bacterial meningitis, and visceral abscess.
Time frame: For the duration of the study, up to approximately 29 months
Population: The Intention-To-Treat (ITT) data set comprised all subjects treated with the study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro10 | Annualized Rate of Acute Serious Bacterial Infections. | 0.018 Infections per subject year |
Secondary
Annualized Rate of Any Infection.
The annualized rate was based on the total number of infections and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days. Infections were classified as all AEs with the system organ class infections and infestations and AEs with the preferred term conjunctivitis.
Time frame: For the duration of the study, up to approximately 29 months.
Population: The ITT data set comprised all subjects treated with the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IgPro10 | Annualized Rate of Any Infection. | 1.600 Infections per subject year |
Secondary
Number of Days of Hospitalization.
Time frame: For the duration of the study, up to approximately 29 months
Population: The ITT data set comprised all subjects treated with the study drug. The patient diary (in which the number of days was recorded) was not available for 1 subject so the analyzed population was reduced from 55 to 54 subjects for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IgPro10 | Number of Days of Hospitalization. | 0.0 Days |
Secondary
Number of Days Out of Work / School / Kindergarten / Day Care or Inability to Perform Normal Activities Due to Illness.
Time frame: For the duration of the study, up to approximately 29 months.
Population: The ITT data set comprised all subjects treated with the study drug. The patient diary (in which the number of days was recorded) was not available for 1 subject so the analyzed population was reduced from 55 to 54 subjects for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IgPro10 | Number of Days Out of Work / School / Kindergarten / Day Care or Inability to Perform Normal Activities Due to Illness. | 8.5 Days |
Secondary
Trough Levels of Total Immunoglobulin (IgG) Serum Concentrations.
Mean IgG trough concentration. For this analysis, each subject's values were first aggregated to their median and the median values were then analyzed.
Time frame: Prior to each infusion; every 3 or 4 weeks depending upon the dosing schedule.
Population: The ITT data set comprised all subjects treated with the study drug for which serum IgG information was available.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IgPro10 | Trough Levels of Total Immunoglobulin (IgG) Serum Concentrations. | 9.72 g/L |