Safety and Pharmacokinetics of IGSC 20% in Subjects With Primary Immunodeficiency

Study Overview
=================
Brief Summary
-----------------
This study was designed to determine a dose of weekly subcutaneously administered Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols) (IGSC 20%) that produces steady-state AUC of total IgG that was non-inferior to that of the regularly administered intravenous dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols) (IGIV-C 10%) in primary immunodeficiency subjects. This study was also designed to determine steady state trough total IgG levels after IGSC 20% infusion and after IGIV-C 10% infusion for comparison and to assess the safety and tolerability of IGSC 20%.

Detailed Description
-----------------
This was a prospective, multi-center, open-label, single-sequence, 6-month, pharmacokinetic, safety and tolerability study of IGSC 20% in subjects with primary immunodeficiency. Approximately 50 subjects were to be enrolled in order to have approximately 30 adult subjects and 12 to 18 pediatric subjects (age 2-16 years) completing treatment with subcutaneously administered IGSC 20%. This study included 3 treatment phases: Run-In Phase, IV Phase (IV administration of IGIV-C 10% treatment), and SC Phase (SC administration of IGSC 20%). Subjects, depending on their current IgG treatment regimen, might be required to enter the Run-In Phase to receive IV IGIV-C 10% treatment (Sponsor provided) to achieve an approximately steady-state condition prior to entering the IV Phase. They then entered the IV Phase to determine the AUC profiles of IV infusions of IGIV-C 10%. Subjects with a qualifying IV IGIV-C 10% treatment regimen (on stable IGIV-C 10% doses of 300-800 mg/kg) entered the IV Phase directly where they will receive IGIV-C 10%. In the IV Phase, steady-state IV PK assessments, including AUC, were to be performed. After completing the IV Phase, subjects entered the SC Phase to receive weekly SC doses of IGSC 20% for at least 24 weeks. The PK profiles of total IgG following administration of both IV (IGIV-C 10%) administration and SC (IGSC 20%) administration were determined and compared after reaching approximate steady-state conditions.

Official Title
-----------------
An Open-label, Multi-center Study to Evaluate the Safety and Pharmacokinetics of IGSC 20% Administered for 6 Months in Subjects With Primary Immunodeficiency

Conditions
-----------------
Primary Immunodeficiency

Intervention / Treatment
-----------------
* Biological: IGIV-C 10%
* Biological: IGSC 20%


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pre-existing diagnosis of primary immunodeficiency with features of hypogammaglobulinemia requiring IgG replacement therapy No serious bacterial infection within the last 3 months prior to or during Screening Currently on IgG replacement therapy (via IV or SC infusion) for ≥3 consecutive months. Subjects receiving IGIV must be receiving a dosage of 300 to 800 mg/kg per infusion Documented (at least once within previous 3 months) IgG trough level of ≥500 mg/dL on current IgG replacement therapy regimen Exclusion Criteria: Known serious adverse reaction to immunoglobulin or any severe anaphylactic reaction to blood or any blood-derived product History of blistering skin disease, clinically significant thrombocytopenia, bleeding disorder, diffuse rash, recurrent skin infections, or other disorders where SC therapy would be contraindicated during the study Isolated IgG subclass deficiency, isolated specific antibody deficiency disorder, or transient hypogammaglobulinemia of infancy Nephrotic syndrome, and/or a history of acute renal failure and/or severe renal impairment, and/or on dialysis History (year prior to Screening or 2 episodes in lifetime ) of or current diagnosis of deep venous thrombosis or thromboembolism (eg, deep vein thrombosis, myocardial infarction, cerebrovascular accident or transient ischemic attack) Acquired medical condition known to cause secondary immune deficiency, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (absolute neutrophil count less than 1000/μL [1.0 x 10^9/L]), or human immunodeficiency virus infection/acquired immune deficiency syndrome Known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus or hepatitis C virus infection Non-controlled arterial hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg in adult subjects) Receiving any of the following medications: (a) immunosuppressants including chemotherapeutic agents, (b) immunomodulators, (c) long-term systemic corticosteroids defined as daily dose >1 mg of prednisone equivalent/kg/day for>30 days Note: Intermittent courses of corticosteroids of not more than 10 days would not exclude a subject. Inhaled or topical corticosteroids are allowed.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IGIV-C 10%<br>IV dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols) | Biological: IGIV-C 10%<br>* IGIV-C 10% infusions every 3 to 4 weeks based on previous IgG regimen<br>* Other names: Immune Globulin Injection 10% Caprylate/Chromatography;|
| Experimental: IGSC 20%<br>Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols) | Biological: IGSC 20%<br>* IGSC 20% weekly infusions with dose calculated based on previous IgG regimen<br>* Other names: Immune Globulin Subcutaneous 20% Caprylate/Chromatography;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC in the IV Phase and SC Phases: Steady-state AUC of Total IgG Over a Regular Dosing Interval | The primary PK endpoint (steady-state AUC values) analysis was performed using analysis of variance (ANOVA) using PK data from a total of 49 subjects from the IV phase and 39 subjects from the SC phase. | For intravenous infusion, predose, 0,1,3-16 hours and 1,2,3,5,7,14,21 or 28 days (2, 7, 21, or 28 days for pediatric subjects) post-dose and for subcutaneous infusion, pre-dose,1,3,4,5,7 days (3 and 7 days for pediatric subjects) post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Steady-state Trough (Pre-dose) Concentration of Total IgG Following IV Administration of IGIV-C 10% or SC Administration of IGSC 20% |  | For intravenous infusion, pre-dose at Week 1 and Week 3 or Week 4 and for subcutaneous infusion, predose at Weeks 13, 14, 17, and 21 |