A Study of Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) in Japanese Participants With Primary Immunodeficiency Diseases (PID)

Study Overview
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Brief Summary
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In this study, Japanese participants with primary immunodeficiency diseases were treated with Immune Globulin Subcutaneous (Human), 20% solution, (IGSC, 20%). This study will be in 3 parts: Part 1: Infusions with Immunoglobulin Intravenous (IGIV) every 3 weeks for 13 weeks. Part 2: Participants will switch to weekly subcutaneous infusions with IGSC, 20% for 24 weeks. Part 3: A subset will receive biweekly subcutaneous infusions with IGSC, 20% for 12 weeks. The main aim of the study is to assess base levels of Immunoglobulin globulin G (IgG) levels in the blood of the participants after weekly and biweekly treatment with IGSC, 20% (in Parts 2 and 3 of the study). Their PID will be treated by their doctor according to their doctor's usual clinical practice.

Detailed Description
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This study consists of 3 treatment parts (Epoch 1, 2, 3). The total evaluation period of the study will be 57 weeks in which screening period is for 2-8 weeks and Epoch 1 is from Week 8 to Week 21, Epoch 2 is from Week 21 to Week 45, Epoch 3 is from Week 45 to Week 57. Each participant will receive IGIV treatment in Epoch 1 for a total of 13 weeks, then switch to weekly subcutaneous (SC) treatment with IGSC, 20% in Epoch 2 for a total of 24 weeks and will continue into Epoch 3 for a total of 12 weeks of biweekly SC treatment with IGSC, 20%. Drug dose in Epoch 2 and Epoch 3 will be adjusted so that it will be an equivalent weekly dose of the dose administered in Epoch 1 and twice the dose administrated in Epoch 2 respectively. Epoch 2 will contain two periods, period 1: dose adjustment period (first 12 weeks) and period 2: evaluation period (second 12 weeks).

Official Title
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A Phase 3, Open-label, Non-controlled, Multi-dose Study to Evaluate the Pharmacokinetics, Safety and Tolerability, and Efficacy of Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) in Japanese Subjects With Primary Immunodeficiency Diseases (PID)

Conditions
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Primary Immunodeficiency Diseases (PID)

Intervention / Treatment
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* Biological: Immune Globulin Intravenous (IGIV)
* Biological: Immune Globulin Subcutaneous, 20% Solution (IGSC, 20%)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese maternal and paternal grandparents. Participants must have a documented diagnosis of a form of primary humoral immunodeficiency involving antibody formation and requiring gammaglobulin replacement. The diagnosis must be confirmed by the medical director prior to treatment with IGIV. Participant is 2 years or older at the time of screening. Written informed consent is obtained from either the participants or the participants legally authorized representative prior to any study-related procedures and study product administration. Participant has been receiving a consistent dose of IGIV over a period of at least 3 months prior to screening equivalent to approximately 200-600 mg/kg-body weight (BW) per 3- 4 week period, as according to the product package insert Participant has a serum trough level of IgG greater than or equal to (>=) 5 gram per liter (g/L) at screening. Participant has not had a serious bacterial infection within the 3 months prior to screening. Participant is willing and able to comply with the requirements of the protocol. Exclusion Criteria: Participant has a known history of or is positive at screening for one or more of the following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1/2. Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent): Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) greater than (>) 2.5 times the upper limit of normal (ULN) for the testing laboratory Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] lesser than or equal to (<=) 500/milli cubic meter [mm^3]). Participant has presence of renal function impairment defined by estimated glomerular filtration rate (eGFR) is less than (<) 60 milliliter per minute/ 1.73 square meter (mL/min/1.73m^2). Participant has been diagnosed with or has a malignancy (other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix), unless the disease-free period prior to screening exceeds 5 years. Participant is receiving anti-coagulation therapy or has a history of thrombotic episodes (including deep vein thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism) within 12 months prior to screening or a history of thrombophilia. Participant has abnormal protein loss (protein losing enteropathy, nephrotic syndrome). Participant has anemia that would preclude phlebotomy for laboratory studies according to standard practice at the site. Participant has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, and/or Immune Serum Globulin (ISG) infusions. Participant has immunoglobulin A (IgA) deficiency (IgA less than 0.07 g/L), known anti IgA antibodies, and a history of hypersensitivity. Participant is on preventative (prophylactic) systemic antibacterial antibiotics at doses sufficient to treat or prevent bacterial infections, and cannot stop these antibiotics at the time of screening. Participant has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening. Participant has a bleeding disorder, or a platelet count less than 20,000/ microliter (mcL), or, in the opinion of the investigator, would be at significant risk of increased bleeding or bruising as a result of subcutaneous therapy. Participant has total protein > 9 gram per deciliter (g/dL) or myeloma, or macroglobulinemia (IgM) or paraproteinemia. Women of childbearing potential meeting any one of the following criteria: Participant presents with a positive pregnancy test. Participant is breast feeding. Participant intends to begin nursing during the course of the study. Participant does not agree to employ adequate birth-control measures (e.g. intrauterine device, diaphragm or condom [for male partner] with spermicidal jelly or foam, or birth control pills/patches) throughout the course of the study. Participant has participated in another clinical study and has been exposed to an IP or device within 30 days prior to study enrollment. Participant is scheduled to participate in another non-observational (interventional) clinical study involving an IP or device during the course of the study. Participant has severe dermatitis that would preclude adequate sites for safe product administration.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epoch 1: Immune Globulin Intravenous (IGIV)<br>Participants will receive approximately 200 to 600 milligrams per kilogram (mg/kg) of Immunoglobulin Globulin Intravenous (IGIV) infusion for every 3 or 4 weeks for a total of 13 weeks. | Biological: Immune Globulin Intravenous (IGIV)<br>* Participants will receive IGIV infusion.<br>* Other names: Immune Globulin Infusion (Human);|
| Experimental: Epoch 2: Immune Globulin Subcutaneous 20% Solution (IGSC)<br>Participants will receive approximately 50 to 200 mg/kg of IGSC infusion, 20 percent (%) once a week for a total of 24 weeks. | Biological: Immune Globulin Subcutaneous, 20% Solution (IGSC, 20%)<br>* Participants will receive IGSC, 20% SC infusion.<br>* Other names: Immune Globulin Infusion (Human);|
| Experimental: Epoch 3: Immune Globulin Subcutaneous 20% Solution (IGSC)<br>Participants will receive approximately 100 to 400 mg/kg of IGSC infusion, 20% once every two weeks in a sub-set of 7 participants for a total of 12 weeks. | Biological: Immune Globulin Subcutaneous, 20% Solution (IGSC, 20%)<br>* Participants will receive IGSC, 20% SC infusion.<br>* Other names: Immune Globulin Infusion (Human);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epoch 2: Total Serum Trough Levels of Immune Globulin G (IgG) Antibodies During Period 2 | Total serum trough levels of IgG antibodies measured during period 2 of Epoch 2 will be assessed. | Epoch 2 (period 2): Up to 21 weeks | 
| Epoch 3: Total Serum Trough Levels of Immune Globulin G (IgG) Antibodies | Total serum trough levels of IgG antibodies measured during Epoch 3 will be assessed. | Epoch 3: Up to Week 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epoch 1: Total Serum Trough Levels of Immune Globulin G (IgG) Antibodies | Total serum trough levels of IgG antibodies measured during Epoch 1 will be assessed. | Epoch 1: Up to Week 13 | 
| Epoch 2: Area Under the Curve (AUC) for Total Serum Levels of IgG and IgG Subclasses | AUC for total serum levels for IgG and IgG Subclasses will be assessed. All Pharmacokinetic (PK) serial sampling will start at Epoch 2 SC infusion at Week 21. | Epoch 2: Week 21: Pre-infusion (Day 0), Day 1, 3, 5, and 7 | 
| Epoch 2: Apparent Clearance (CL/F) for Total Serum Levels of IgG and IgG Subclasses | Cl/F for total serum levels of IgG and IgG Subclasses will be assessed. All PK serial sampling will start at Epoch 2 SC infusion at Week 21. | Epoch 2: Week 21: Pre-infusion (Day 0), Day 1, 3, 5, and 7 | 
| Epoch 2: Maximum Concentration (Cmax) for Total Serum Levels of IgG and IgG Subclasses | Cmax for total serum levels of IgG and IgG Subclasses will be assessed.All PK serial sampling will start at Epoch 2 SC infusion at Week 21. | Epoch 2: Week 21: Pre-infusion (Day 0), Day 1, 3, 5, and 7 | 
| Epoch 2: Minimum Concentration (Cmin) for Total Serum Levels of IgG and IgG Subclasses | Cmin for total serum levels of IgG and IgG Subclasses will be assessed. All PK serial sampling will start at Epoch 2 SC infusion at Week 21. | Epoch 2: Week 21: Pre-infusion (Day 0), Day 1, 3, 5, and 7 | 
| Epoch 2: Time to Maximum Concentration (Tmax) for Total Serum Levels of IgG and IgG Subclasses | Tmax for total serum levels of IgG and IgG Subclasses will be assessed. All PK serial sampling will start at Epoch 2 SC infusion at Week 21. | Epoch 2: Week 21: Pre-infusion (Day 0), Day 1, 3, 5, and 7 | 
| Trough Levels of Specific Antibodies to Clinically Relevant Pathogens | Trough levels of specific antibodies to clinically relevant pathogens (Clostridium tetani toxoid, HIB, HBV) will be assessed in Epoch 1, Epoch 2 and Epoch 3. | Epoch 1 (Week 1); Epoch 2 (Week 1); Epoch 3 (Week 1, 13) | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) | TEAEs is defined as Adverse events (AEs) with onset after date-time of first dose of IP, or medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Any TEAE that is recorded by the investigator as possibly related or probably related to IP will be considered as IGSC, 20%-related AE, and any AE recorded as unlikely related or not related will be considered as unrelated AE. AEs will includes vital signs, clinical laboratory measurements. Number of participants with TEAEs will be assessed. | From start of study up to Week 57 | 
| Number of Participants with Tolerability Events Related to the Infusion of Investigational Product (IP) | An infusion is considered tolerable if the infusion rate was not reduced, or the infusion was not interrupted or stopped, due to IP TEAE related to study drug (IGIV or IGSC) infusion. A tolerability event is considered to have occurred if an infusion was tolerable in Epoch 1, Epoch 2 and Epoch 3. Number of participants with tolerability events related to infusion of IP will be assessed. | From start of study up to Week 57 | 
| Annual Rate of Validated Acute Serious Bacterial Infections (ASBI) | The ASBI rate will be calculated as the mean number of acute serious bacterial infections per participants per year. Annual rate of validated acute serious bacterial infections per subject will be assessed. | From start of study up to Week 57 | 
| Annual Rate of All Infections | Annual rate is the number of participants reporting any infection per year. | From start of study up to Week 57 | 
| Number of Days Participants not Able to Attend School or Work to Perform Normal Daily Activities due to Illness/Infection | Number of days not able to attend school or work to perform normal daily activities due to illness/infection will be assessed. | From start of study up to Week 57 | 
| Number of Days Participants on Antibiotics | Number of days participants on antibiotics will be assessed. | From start of study up to Week 57 | 
| Number of Participants Hospitalized due to Illness or Infection | Number of participants will report hospitalizations due to illness or infection will be assessed. | From start of study up to Week 57 | 
| Length of Hospital Stay | Number of days participants stay in hospital. | From start of study up to Week 57 | 
| Number of Participants will Report Acute Physician Visits due to Illness/Infection | Number of participants will report acute (urgent or unscheduled) physician visits due to illness or infection will be reported. | From start of study up to Week 57 | 
| Health-related Quality of Life (HRQoL): Pediatric Quality of Life Inventory (PedsQL) | The Peds-QL is a generic Health-Related Quality of Life (HR QoL) instrument designed specifically for a pediatric population. It captures the following domains: general health/activities, feelings/emotional, social functioning, school functioning. In this study, 2-7 years (parent as observer), 8-13 years (participant as observer) for Peds-QL health questionnaire will be analyzed. Higher scores indicate better quality of life (QOL) for all domains of the Peds-QL. This modular instrument uses a 5-point scale: from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Four dimensions (physical, emotional, social, & school functioning) are scored. | Epoch 1 (Week 1); Epoch 2 (Week 1); Epoch 3 (Week 1, 13) | 
| EuroQoL (Quality of Life)-5 Dimensions 3 Levels (EQ-5D-3L) | EQ-5D-3L health questionnaire is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. In this study, 2-11 years (parent as observer),12 years and older (participant as observer) for EQ-5D-3L health questionnaire will be analyzed. The EQ-5D-3L total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome. | Epoch 1 (Week 1); Epoch 2 (Week 1); Epoch 3 (Week 1, 13) | 
| Health-related Quality of Life (HRQoL): Short Form-36 Health Survey (SF-36) | The SF-36 is a generic quality-of-life instrument that has been widely used to assess health-related quality of life (HRQL) of participants. In this study, 14 years and older (participant as observer) for SF-36 health questionnaire will be analyzed. Generic instruments are used in general populations to assess a wide range of domains applicable to a variety of health states, conditions, and diseases. The SF-36 consists of 36 items that are aggregated into 8 multi-item scales (physical functioning, role - physical, bodily pain, general health, vitality, social functioning, role - emotional, and mental health), with scores ranging from 0 to 100. Higher scores indicate better HRQL. | Epoch 1 (Week 1); Epoch 2 (Week 1); Epoch 3 (Week 1, 13) | 
| Health Related Quality of Life: Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) | Treatment Satisfaction Questionnaire for Medication (TSQM) is a global satisfaction scale used to assess the overall level of participant's satisfaction or dissatisfaction with their medications. In this study, 2-12 years (parent as observer), 13 years and older (participant as observer) for TSQM health questionnaire will be analyzed. TSQM-9 is a 9-item, validated, self-administered instrument used to assess participant's satisfaction with medication. The three domains assessed are effectiveness, convenience, and global satisfaction. The score of each of the 3 domains is based on an algorithm to create a score of 0 to 100. Higher score indicated greater satisfaction in that domain. | Epoch 1 (Week 1); Epoch 2 (Week 1); Epoch 3 (Week 1, 13) | 
| Health Related Quality of Life: Treatment Satisfaction Questionnaire for Life Quality Index (LQI) | The LQI is a self-administered questionnaire developed specifically for participants/legal guardians involved in IGIV treatments. In this study, 2-13 years (parent as observer), 14 years and older (participant as observer) for LQI health questionnaire will be analyzed. LQI consists of 15-items, divided into four domains: treatment interferences (6 items), therapy-related problems (4 items), therapy setting (3 items), and treatment costs (2 items). Items are rated on a 7-point Likert-type scale ranging from 1: Extremely bad to 7: Extremely good. Total scores range from 15 to 105, with higher scores indicating the highest possible satisfaction with factors such as independence, therapy convenience, social/school/work activities, and health and travel costs. | Epoch 1 (Week 1); Epoch 2 (Week 1); Epoch 3 (Week 1, 13) | 
| Health Related Quality of Life: Treatment Preference | Treatment preference questionnaire is a self-administered questionnaire developed to assess participants' preference towards the administration of new IGSC therapy. There are 4-items on the questionnaire, which investigate a participant's preference on the clinic/hospital/home setting of receiving the immunoglobulin therapy, the participant's rating on the frequency and method of administration, and the participant's preference to continue receiving the IGSC treatment. | Up to Week 57 |