Study to Evaluate Safety and Pharmacokinetics of BIVIGAM® in Primary Immune Deficiency Subjects Aged 2 to 16

Study Overview
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Brief Summary
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This study is part of the BIVIGAM® post marketing requirement (PMR). It is being conducted in subjects aged 2-16 with primary immune deficiency disorders associated with defects in humoral immunity to generate additional data on these populations, and more specifically safety and pharmacokinetic (PK) assessments.

Official Title
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A Phase IV, Multicenter, Open-label Study to Evaluate the Safety and Pharmacokinetics of BIVIGAM® in Primary Immune Deficiency Disorders in Subjects Aged 2 to 16

Conditions
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Humoral Immune Response

Intervention / Treatment
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* Biological: Bivigam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent/Assent Male or female between 2 and 16 years, inclusive, at time of Signing Informed Consent/Assent Have a confirmed and documented clinical diagnosis of Primary Immune Deficiency Disorder, including hypogammaglobulinemia or agammaglobulinemia. Have received IGIV therapy which was maintained at a steady dose (± 25% of the mean dose) for at least 3 months prior to study entry, and have maintained a trough IgG level at least 500mg/dL prior to receiving BIVIGAM®. Subjects and/or parents/legal guardians must be able to understand and adhere to the study visit schedule and all other protocol requirements. Exclusion Criteria: Known intolerance to immunoglobulins or comparable substances (e.g. vaccination reaction). Known intolerance to proteins of human origin or known allergic reactions to components of the study product(s). Any previous randomization/participation in this clinical study must be discussed with and approved by the medical director (or designee). Inability or lacking motivation to participate in the study. Medical condition, laboratory finding, or physical exam finding (specify, e.g., vital signs outside of specific range that precludes participation. Per lab results at the Screening visit through Baseline. Confirmed Screening visit laboratory results ˃2.5 X ULN as defined for pediatric populations for any of the following: ALT (alanine aminotransferase/SGPT), AST (aspartate aminotransferase/SGOT), LDH (lactate dehydrogenase), BUN (blood urea nitrogen), Serum creatinine Has selective IgA deficiency or demonstrated antibodies to IgA. History of thrombotic complications of IGIV therapy or history of (deep vein thrombosis)DVT. Current use of daily corticosteroids (>10 mg of prednisone equivalent/day),immunosuppressants or immunomodulators are not allowed unless approved in advance by the medical monitor. Intermittent use of corticosteroids during the study is allowed if medically necessary. Positive diagnosis of hepatitis B or hepatitis C. Positive human immunodeficiency virus (HIV) test. Subject has had a serious bacterial infection (SBI) within the last 3 months. Subject has an active infection and is receiving antibiotic therapy for the treatment of this infection at the time of Screening. Note: if the subject is deemed a Screen Failure due to a nonserious active infection requiring antibiotic therapy, the subject may be rescreened 3 or 4 weeks (depending on drug administration schedule) after the initial screening. Subject has a history of thrombotic events (including deep vein thrombosis, myocardial infarction, cerebrovascular accident and pulmonary embolism) within 6 months before 1st IGIV dose or has preexisting risk factors for thrombotic events. Acquired medical condition known to cause secondary immune deficiency such as chronic lymphacitic leukemia, lymphoma or multiple lymphoma. Subjects with protein-losing enteropathies, hypoalbuminaemia. Females taking oral contraceptives. Pregnancy or unreliable contraceptive measures or lactation period (females of childbearing potential (female capable of becoming pregnant) only. Males capable of reproduction must agree to a double barrier method of contraception during their study participation.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Active Drug<br>All subjects will receive Bivigam based on their prior dosing to be adjusted as clinically necessary. | Biological: Bivigam<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Temporally Associated Adverse Events | Incidence of adverse events (During or within 1 hour, 24 hours and 72 hours of completion of an infusion) | During each infusion (During or within 1 hour, 24 hours and 72 hours of completion of an infusion) | 
| Number of Temporally Associated Adverse Events | Mean number of temporally associated per infusion | Up to 72 hours of completion of an infusion | 
| Serious Adverse Events | Incidence of serious adverse events | Up to approximately 7 months | 
| Related Serious Adverse Events | Incidence of related serious adverse events | Up to approximately 7 months | 
| Treatment Emergent Adverse Events | Incidence of treatment emergent adverse events | Up to approximately 7 months | 
| Related Treatment Emergent Averse Events | Incidence of adverse events that first appear, or that worsen relative to the pre-treatment state, which occur during and within 72 hours of treatment administration | Within 72 hours of infusion | 
| Non-treatment Emergent Adverse Events | Incidence of adverse events which do not have a causal relationship with study treatment | Up to approximately 7 months | 
| Temporally Associated Infusion Adverse Events | Incidence of adverse events which have a causal relationship with infusion treatment | Up to approximately 7 months | 
| Adverse Reactions | Number and incidence of adverse reactions plus suspected adverse reactions combined | Up to approximately 7 months | 
| Related Adverse Reactions | Incidence of adverse infusion related reactions | Up to approximately 7 months | 
| Infusion Site Reactions | Incidence reactions occuring at the infusion site | Up to approximately 7 months | 
| Vital Signs | Change in vital signs | Before and after each administration of study drug through study completion, up to approximately 7 months | 
| Temporally Associated Adverse Events Following Infusions | Incidence of adverse events | Up to 72 hours after each infusion through study completion, up tp approximately 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total IgG Trough | Levels taken before any infusion | At each visit through study completion, up tp approximately 7 months | 
| IgG subclasses | Levels of subclasses 1- 4 before infusion | Prior to first and last infusion, up tp approximately 7 months | 
| Total IgG Post | End of infusion level of Total IgG | At each infusion through study completion, up tp approximately 7 months | 
| Cmax | Pharmacokinetic measure at 5th or 7th infusion | At prior to, at end of infusion, and 6 hours, 24 hours, 7 days, and 4 days, 21 days and 28 days (if still enrolled) after final infusion, up tp approximately 7 months | 
| Tmax | Pharmacokinetic measure at 5th or 7th infusion | At prior to, at end of infusion, and 6 hours, 24 hours, 7 days, and 4 days, 21 days and 28 days (if still enrolled) after final infusion, up tp approximately 7 months | 
| AUC(0-ʈ) | Pharmacokinetic measure at 5th or 7th infusion | At prior to, at end of infusion, and 6 hours, 24 hours, 7 days, and 4 days, 21 days and 28 days (if still enrolled) after final infusion, up tp approximately 7 months | 
| AUC(0-∞) | Pharmacokinetic measure at 5th or 7th infusion | At prior to, at end of infusion, and 6 hours, 24 hours, 7 days, and 4 days, 21 days and 28 days (if still enrolled) after infusion | 
| Terminal phase elimination half-life (ʈ½) | Pharmacokinetic measure at 5th or 7th infusion | At prior to, at end of infusion, and 6 hours, 24 hours, 7 days, and 4 days, 21 days and 28 days (if still enrolled) after final infusion, up tp approximately 7 months | 
| Antibodies | Levels of specific antibodies (antipneumococcal capsular polysaccharide, antihaemophilus influenza B | At prior to, at end of infusion, and 6 hours, 24 hours, 7 days, and 4 days, 21 days and 28 days (if still enrolled) after final infusion, up tp approximately 7 months | 
| Infections | Number of infections of any kind, serious and non-serious | Up to approximately 7 months | 
| First Serious Bacterial Infection | Time to first Serious Bacterial Infections in days | Up to approximately 7 months | 
| Serious Bacterial Infections | Incidence of Serious Bacterial Infections | Up to approximately 7 months | 
| Other Infections | Incidence of infections other than Serious Bacterial Infections | Up to approximately 7 months | 
| Resolution of Infections | Time to resolution of Infections in days | Up to approximately 7 months | 
| Fever | Episodes of Fever | Up to approximately 7 months | 
| Missed Days | Number of days missed of school or work due to infections and treatment | Up to approximately 7 months | 
| Hospitalizations | Number of hospitalizations due to infections | Up to approximately 7 months | 
| Terminal phase elimination rate (λZ) | Pharmacokinetic measure at 5th or 7th infusion | At prior to, at end of infusion, and 6 hours, 24 hours, 7 days, and 4 days, 21 days and 28 days (if still enrolled) after final infusion, up tp approximately 7 months |