Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)

Study Overview
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Brief Summary
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This multicenter, open-label, parallel-arm, non-randomized study is designed to evaluate safety and tolerability of higher infusion parameters of IgPro20 in subjects with primary immunodeficiency (PID). A total of 45 subjects (including at least 14 [30%] pediatric subjects ≤ 17 years of age and at least 9 [20%] obese subjects with body mass index [BMI] of ≥30 kg/m2) with confirmed PID will be evaluated in the study. The study will include three cohorts of 15 subjects each as follows: i) Pump-Assisted Volume Cohort (weekly infusions), volume per injection site of 25 mL up to 50 mL, ii) Pump Assisted Flow Rate Cohort (weekly infusions), flow rate per injection site of 25 mL/hour up to 100 mL/hour, iii) Manual Push Flow Rate Cohort (2 to 7 infusions per week), flow rate per injection site of 25 to 30 mL/hour up to 120 mL/hour (equivalent of approximately 0.5 mL/minute up to 2 mL/minute). Each cohort will test 3 infusion parameter levels (4 for the pump-assisted flow rate cohort), repeated at least 4 times over a duration of 12 weeks (16 weeks for the flow rate cohort). After 4 infusion weeks at each level, qualifying subjects (responders) will switch to the next infusion parameter level (eg, from 25 to 50 mL/h). During the study, the weekly dose will remain unchanged (as prescribed by treating physician, usually within 100-200 mg/kg per week range); only the respective infusion parameter under evaluation will change.

Official Title
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An Open-label Multicenter Study to Evaluate the Safety and Tolerability of Higher Infusion Parameters of Immune Globulin Subcutaneous (Human), 20% Liquid (Hizentra®) in Subjects With Primary Immunodeficiency

Conditions
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Primary Immunodeficiency

Intervention / Treatment
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* Drug: IgPro20


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female on stable dose of IgPro20 (Hizentra) therapy. Women of childbearing potential must be using and agree to continue using medically approved contraception (which must be discussed with the study doctor) and must have a negative pregnancy test at screening. Subjects with PID, eg, with a diagnosis of common variable immunodeficiency or X-linked agammaglobulinemia, as defined by the Pan American Group for Immune Deficiency and the European Society of Immune Deficiencies. With infusion parameters as specified below: Pump-Assisted Flow Rate Cohort subjects only Experience with pump-assisted infusions of IgPro20 at the tolerated flow rate of 25 mL/h per injection site for at least 1 month prior to Day 1. Pump-Assisted Volume Cohort subjects only Total weekly IgPro20 dose of ≥ 50 mL (≥ 10 g). Experience with pump-assisted infusions of IgPro20 at tolerated volumes of 25 mL/injection site for at least 1 month prior to Day 1. Manual Push Flow Rate Cohort subjects only Experience with frequent (2-7 times per week) infusions of IgPro20 at the tolerated flow rate of approximately 0.5 mL/min (equivalent of 25-30 mL/h) per injection site for at least 1 month prior to Day 1. The dose (volume) per injection site should not exceed 25 mL. Exclusion Criteria: Ongoing serious bacterial infections at the time of screening. Other significant medical conditions that could increase the risk to the subject. Females who are pregnant, breast feeding, or planning a pregnancy during the course study. Participation in a study with an Investigational Medicinal Product (IMP) other than IgPro20 within three months prior to enrollment.

Ages Eligible for Study
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Minimum Age: 2 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IgPro20 (Pump-Assisted Volume Cohort)<br>Weekly volumes per injection site of 25 mL up to 50 mL administered subcutaneously. | Drug: IgPro20<br>* A liquid formulation of normal human IgG at a concentration of 20% administered as a subcutaneous infusion at a dose prescribed by subject's physician prior to study entry.<br>* Other names: Hizentra;|
| Experimental: IgPro20 (Pump Assisted Flow Rate Cohort)<br>Weekly flow rates per injection site of 25 mL/hour up to 100 mL/hour administered subcutaneously. | Drug: IgPro20<br>* A liquid formulation of normal human IgG at a concentration of 20% administered as a subcutaneous infusion at a dose prescribed by subject's physician prior to study entry.<br>* Other names: Hizentra;|
| Experimental: IgPro20 (Manual Push Flow Rate Cohort)<br>Frequent (ie, 2 to 7 times per week) flow rates per injection site of 25 to 30 mL/hour up to 120 mL/hour (equivalent of approximately 0.5 mL/minute up to 2 mL/minute) administered subcutaneously. | Drug: IgPro20<br>* A liquid formulation of normal human IgG at a concentration of 20% administered as a subcutaneous infusion at a dose prescribed by subject's physician prior to study entry.<br>* Other names: Hizentra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders | A responder is a subject within the Pump-Assisted Cohorts that performs at least 3 out of 4 valid infusions at a certain infusion parameter level (weekly volumes per injection site of 25-50 mL; weekly flow rates per injection site of 25-100 mL/hour). Determination of a responder in the Manual Push Cohort is more complex due to the expected variable frequency of infusions per week (ie, 5-17) for different subjects. A responder within the Manual Push Cohort is a subject that performs a minimum number of valid infusions during 4 weeks corresponding to a certain flow rate level ([ie, 2-7 times per week], flow rates per injection site of 30-120 mL/hour). Valid infusions do not need to be consecutive, but each subject needs to adhere to the same schedule (number of infusions per week) throughout the study. An infusion parameter will be considered successful if at least one third (≥ 33%) of the subjects in the corresponding cohort are responders at that infusion parameter level. | At the end of 4 weeks for each planned infusion parameter | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Treatment-emergent Adverse Events (TEAEs) Per Infusion | Adverse event rate per infusion = number of adverse events/total number of infusions prior to subject's start date of non-response. Only events are included which start prior to subject's start date of non-response. | At the end of 4 weeks for each planned infusion parameter | 
| Rate of Local TEAEs Per Infusion | Local adverse event rate per infusion = number of local adverse events/total number of infusions prior to subject's start date of non-response. Local Adverse Events: comprises all events reported within the MedDRA high level terms administration site reactions NEC (Not Elsewhere Classified), infusion site reactions, and injection site reactions. Only events are included which start prior to subject's start date of non-response. | At the end of 4 weeks for each planned infusion parameter | 
| Time to Onset of Local TEAEs | Local Adverse Events: comprises all events reported within the MedDRA high level terms administration site reactions NEC, infusion site reactions, and injection site reactions. Only events are included which start prior to subject's start date of non-response. | At the end of 4 weeks for each planned infusion parameter | 
| Intensity of Local TEAEs | Mild = A type of AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living. Moderate = A type of AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the subject. Severe = A type of AE that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Only events are included which start prior to subject's start date of non-response. | At the end of 4 weeks for each planned infusion parameter | 
| Duration of Local TEAEs | Local Adverse Events: comprises all events reported within the MedDRA high level terms administration site reactions NEC, infusion site reactions, and injection site reactions. | At the end of 4 weeks for each planned infusion parameter | 
| Tolerability of Infusions | Tolerability = number of infusions without severe local adverse events / total number of infusions. Severe = A type of AE that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Only events are included which start prior to subject's start date of non-response. | At the end of 4 weeks for each planned infusion parameter |