Primary Immunodeficiency
Conditions
Brief summary
The purpose of this open-label study is to evaluate the pharmacokinetics, safety, and tolerability of subcutaneously (SC; under the skin) administered GAMUNEX-C compared to intravenously (IV; through the vein) administered GAMUNEX-C in subjects 2-16 years of age with Primary Immunodeficiency.
Detailed description
This study was a multi-center, open-label, single-sequence, crossover study to evaluate the pharmacokinetics (PK), safety and tolerability of SC-administered GAMUNEX-C in pediatric PI subjects (ages 2-16). The study consisted of a Screening Phase, Run-in Phase, two treatment phases (an IV Phase and a SC Phase), and an End of Study/Early Termination (EOS/ET) visit. Run-in phase: 3 - 4 months, IV Phase: \ 4 - 5 weeks, SC Phase: 12 weeks, and End of Study/Early Termination (EOS/ET) visit: one week after SC Week #12.
Interventions
BIOLOGICALGAMUNEX-C
GAMUNEX-C Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified, Intravenous Administration: 200-600 mg/kg per intravenous infusion every 3-4 weeks
Sponsors
Grifols Therapeutics LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Aged 2-16 years old, inclusive. * Documented and confirmed pre-existing diagnosis of PI with features of hypogammaglobulinemia requiring immunoglobulin replacement. * Currently on IgG replacement therapy with a serum IgG trough concentration of ≥ 500 mg/dL at the Screening Visit. * Adequate normal skin to allow for SC infusions. * Signs an assent form, if applicable (per Institutional Review Board \[IRB\] requirements). Parent or legal guardian must sign an informed consent form. * Females of childbearing potential must have a negative urine pregnancy test result and must practice an effective form of contraception (which may include abstinence).
Exclusion criteria
* History of anaphylaxis or severe systemic response to an immunoglobulin or blood product. * History of blistering skin disease, clinically significant thrombocytopenia, bleeding disorder, recurrent skin infections or other disorders where subcutaneous therapy could be contraindicated. * Has a specific antibody deficiency disorder, IgG subclass deficiency, or transient hypogammaglobulinemia of infancy. * History of severe adverse reaction to parenteral products containing immunoglobulin A (IgA). * Significant proteinuria and/or has a history of acute renal failure and/or severe renal impairment (serum creatinine more than 2.5 times the upper limit of normal \[ULN\] for age and gender) and/or is on dialysis. * Known substance or prescription drug abuse in the past 12 months. * Acquired medical condition that is known to cause secondary immune deficiency. * Receiving any of the following medications: systemic corticosteroids (long term daily, \>1 mg of prednisone equivalent/kg/day for \>30 days) (intermittent courses would not exclude subject); immunosuppressants (i.e., antimetabolites and systemic calcineurin inhibitors; NOTE: inhaled steroids are allowed); or immunomodulators. * Non-controlled arterial hypertension at a level of ≥ the 90th percentile blood pressure (either systolic or diastolic) for age and height (based on http://www.nhlbi.nih.gov/guidelines/hypertension/child\_tbl.pdf ). * History or current diagnosis of thrombotic episodes; venous thrombus that occurred in association with a medical device \> 2 years prior to screening are allowed. * Currently receiving anti-coagulation therapy. * History of Kawasaki disease. * Participated in another clinical trial involving exposure to an investigational product or device within 30 days prior to screening (imaging studies without investigative treatments are permitted) or has received any investigational blood product within the previous 3 months. * Unable or unwilling to comply with any aspect of the protocol, including blood sampling and completion of the Infusion Site Reactions pages in the SC Infusion Diary. * In the opinion of the Investigator the subject may have compliance problems with the protocol and the procedures of the protocol. * Pregnant or lactating. * Clinical evidence of any significant acute or chronic disease that, in the opinion of the Investigator, may interfere with successful completion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steady-state Area Under the Curve (AUC) for Serum Total Immunoglobulin (IgG) | 4 to 5 weeks for IV administration; 12 weeks for SC administration | Steady-state area under the curve (AUC): For the IV phase, the mean adjusted AUC was calculated for all 11 subjects, which included subjects on both 3 and 4 week intravenous (IV) dosing schedules and who had sufficient immunoglobulin G (IgG) data. For the SC phase, the mean AUC was calculated for 10 subjects on weekly subcutaneous (SC) administration and who had sufficient IgG data. |
| Mean Trough of Serum Total IgG | 4 - 5 weeks of IV administration and 12 weeks for SC administration | Mean trough serum total IgG values were calculated for each subject for the IV Phase (IV #1 and IV #2) and the SC phase (SC Weeks #9 and #12, and End of Treatment/Early termination visit). Mean trough concentration values of serum total IgG during the IV and SC phases were calculated based on the IgG population (subjects who received any amount of study drug and had serum total IgG concentration data). |
Countries
United States
Participant flow
Recruitment details
A total of 13 subjects were screened for participation in this study. After screening, one subject discontinued the study and did not receive study drug. Eleven subjects entered the Run-in phase. One subject entered intravenous Gamunex-C phase directly. A total of 11 subjects entered the IV phase and subsequently entered the SC phase.
Participants by arm
| Arm | Count |
|---|---|
| Safety Population The safety population consisted of all subjects who received any amount of GAMUNEX-C. In the Run-in Phase, subjects received intravenous infusions of Gamunex-C at a dose between 200 to 600 mg/kg every three or four weeks for 3 months. In the subsequent IV phase, subjects received two IV infusions of Gamunex-C at a dose between 200 to 600 mg/kg for four to five weeks. In the SC Phase, subjects received weekly subcutaneous infusion of Gamunex-C at a mg/kg dose based on intravenous dose of the subject and dosing interval x 1.37 conversion factor for 12 weeks. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Run-in Phase | Protocol Violation | 1 | 0 |
| Subcutaneous (SC) Phase | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Safety Population |
|---|---|
| Age, Categorical <=18 years | 12 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 10.8 years STANDARD_DEVIATION 3.7 |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 12 | 11 / 11 |
| serious Total, serious adverse events | 0 / 12 | 1 / 11 |
Outcome results
Primary
Mean Trough of Serum Total IgG
Mean trough serum total IgG values were calculated for each subject for the IV Phase (IV #1 and IV #2) and the SC phase (SC Weeks #9 and #12, and End of Treatment/Early termination visit). Mean trough concentration values of serum total IgG during the IV and SC phases were calculated based on the IgG population (subjects who received any amount of study drug and had serum total IgG concentration data).
Time frame: 4 - 5 weeks of IV administration and 12 weeks for SC administration
Population: The IgG Population was used to calculate the trough serum concentrations. The IgG population consisted of all subjects who received any amount of GAMUNEX-C and had any serum total IgG concentration data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intravenous GAMUNEX-C | Mean Trough of Serum Total IgG | 997.2 mg/dL |
| Subcutaneous GAMUNEX-C | Mean Trough of Serum Total IgG | 1325.0 mg/dL |
Primary
Steady-state Area Under the Curve (AUC) for Serum Total Immunoglobulin (IgG)
Steady-state area under the curve (AUC): For the IV phase, the mean adjusted AUC was calculated for all 11 subjects, which included subjects on both 3 and 4 week intravenous (IV) dosing schedules and who had sufficient immunoglobulin G (IgG) data. For the SC phase, the mean AUC was calculated for 10 subjects on weekly subcutaneous (SC) administration and who had sufficient IgG data.
Time frame: 4 to 5 weeks for IV administration; 12 weeks for SC administration
Population: The PK population included the subjects with the availability of sufficient pharmacokinetics (PK) data to calculate area under the curve (AUC) for either the IV or SC phases.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intravenous GAMUNEX-C | Steady-state Area Under the Curve (AUC) for Serum Total Immunoglobulin (IgG) | 216873.7 h*mg/dL |
| Subcutaneous GAMUNEX-C | Steady-state Area Under the Curve (AUC) for Serum Total Immunoglobulin (IgG) | 230830.0 h*mg/dL |