Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG

Study Overview
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Brief Summary
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To evaluate the safety, efficacy, and pharmacokinetic properties of Shu Yang intravenous immune globulin in patients with primary immune deficiency aged less than 60 years. The main benefit of IVIG is to help the body fight against a large variety of infections generally associated with morbidity and mortality in patients with primary immunodeficiency diseases, particularly in CVID and XLA. In addition, a decrease in the number of infections, a reduction in medications and hospitalizations, and a better quality of life are expected. Throughout treatment, approximately one-fourth of persons may experience a side effect. These are usually mild or bothersome but not dangerous. Very rarely, more serious side effects like allergic reactions or low blood counts (anemia) can occur. One of the most common side effects is headache. Other side effects include chills, fever, flushing, flu-like muscle pains or joint pains, feeling tired, nausea, vomiting, and rash. For the most part, these reactions typically happen with the first dose of IVIG or because change to a different brand of IVIG. All IVIG products have similar warnings and contraindications, such as the potential for renal failure, thrombotic events, aseptic meningitis, hemolysis, and anaphylactic reactions.

Detailed Description
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This is a Phase III, open-label, prospective, single-arm, multicenter trial to evaluate the efficacy of IVIG in maintaining the average of severe bacterial infections in less than one per year. The safety and pharmacokinetics (PK) of the investigational product will also be evaluated. Fifty male or female patients aged up to 60 years old will be selected. At least 20 patients must be up to 17 years old. During the trial, at least 20 adult patients will be invited to make up the PK assessment subgroups. After obtaining the signed Informed Consent/Assent Form , the screening procedures will be performed including the immune deficiency history from the medical records and safety exams. Patients will start the trial with a run-in period to stabilize the IgG trough levels. This period could last two to six visits with posological adjustments until the last two IgG trough levels are above 4 (5) g/L. After the run-in, the one-year test period will start at the V0. Depending on the treatment regimen, the patients will receive IVIG every 21 days (±3 days) up to day 378 or every 28 days (±4 days) up to day 364 when the close-out visit will occur. In all visits from all patients, a blood sample will be collected immediately before each IVIG administration to assess the IgG trough levels. To assess the investigational product PK properties, a group of 20 patients will collect additional blood samples for dosing IgG levels between Visit 4 and Visit 5. Those taking IVIG every 21 days, will collect six additional blood samples at the following times after the injection 30 min, 2h, 24h, 72h, 7 days, and 14 days. Those taking IVIG every 28 days will collect seven additional blood samples at the times 30 min, 2h, 24h, 72h, 7 days, 14 days, and 21 days. Adverse events will be collected at all visits to fulfill the safety endpoints. Moreover, the patients will have continuous access to the investigator's team to report adverse events, be instructed about how to proceed, or even perform Extra visits for presential medical evaluation. Additionally, the patient will receive a diary to record AEs, any medication taken, infections of any kind, days of hospitalization, and days missed from major activities due to infections. Trial duration: Each patient can participate in the trial for a maximum period of approximately 540 days from the time of signing the ICF or IAF until the close-out visit, including a Run-in period, depending on treatment regimen. Blinding and Randomization: This is an open-label trial; no blinding and randomization procedures will be applied.

Official Title
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Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG in Patients With Primary Immunodeficiency

Conditions
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Primary Immunodeficiency Disease

Intervention / Treatment
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* Biological: IVIG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent/assent. Male or female. Ages ≤ 60 years old and ≥ 06 years old. Diagnosis of Primary Immunodeficiency Disease (PID) with a reduction in antibody production due to: a. Common Variable Immunodeficiency (CVID) as per European Immunodeficiency Society (ESID)/Pan American Immunodeficiency Group (PAGID), as defined in section 5.1, OR b. X-linked agammaglobulinemia (XLA) as per ESID/PAGID, as defined in section 5.1. Receiving replacement therapy with intravenous immunoglobulin at 21- to 28-day intervals at 300-600 mg/kg/month for a minimum of 2 months before the start of the study; Absence of episodes of serious bacterial infections with previous use of an IV immunoglobulin for at least 3 months before screening; Negative pregnancy test (in female patients with childbearing potential); readiness to use reliable methods of contraception throughout the study period; Patients who participated in a clinical trial with another experimental IVIG may be enrolled if they have a potential benefit according to Res. CNS 251/1997; Patients currently on treatment with any subcutaneous or intramuscular immunoglobulin may be enrolled switching to IVIG therapy at the investigator's discretion, considering the potential benefit to the patient. Exclusion Criteria: Known intolerance or hypersensitivity to immunoglobulins or components of the test article; Any contraindications to the use of immunoglobulins; Secondary immunodeficiency or conditions potentially causing secondary immunodeficiency such as chronic lymphoid leukemia, lymphoma, multiple myeloma, protein-losing enteropathies or nephropathies, and hypoalbuminemia; Clinically relevant changes in the safety exams are defined as: Blood count o Hb < 10.5 g/dL o Leukocytes < 3,000 /uL or >10,000 cells / uL o Absolute neutrophil count < 1,000 cells/mm3; Coagulation o TP and aPTT > 2.5 x ULN Biochemistry o glycated hemoglobin > 6.5% total bilirubin and fractions, alkaline phosphatase, ALT, AST, GGT > 2.5 x ULN creatinine above 3mg/dl or creatinine clearance < 30mL/min Urine I. Leukocyturia > 10,000 cells/mL 5. Any cancer either active or resolved within the last 12 months before screening; 6. Receiving any blood products (except intravenous immunoglobulins) during the last 3 months before screening; 7. Any febrile illness within 14 days before enrollment; Note: The patient may be rescreened after recovery. 8. History of thrombotic events (including myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis) within 6 months before enrollment; 9. Previous use of live attenuated virus vaccines; 10. Selective deficiency of immunoglobulin A (IgA) or known antibodies to IgA; 11. Known drug or alcohol abuse; 12. The need to use other investigational drugs, systemic immunosuppressants, and any other immunoglobulins; 13. Pregnancy or lactation; 14. Inability to comply with the protocol activities; 15. PIDs other than CVID or X-linked agammaglobulinemia 16. Patients infected with HIV, HBV or HCV 17. Patients with AIDS, cystic fibrosis, or active hepatitis B or C. 18. Any other condition that, in the Investigator's opinion may increase the risk of participation in this study.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 60 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
Intervention Model: Single Group Assignment
Interventional Model Description: Patients with primary immunodeficiency will switch to Shu Yang IVIG and optimize the posology in a run-in period of 2 to 6 administrations. In the one-year test period, the patients will receive the test IVIG at 21- or 28-day intervals and be followed. IgG trough levels will be collected at all visits. At Visit 4, at least 20 patients will perform the PK assessment, collecting additional blood samples.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IVIG<br>Patients with primary immunodeficiency will switch to Shu Yang IVIG and optimize the posology to IgG 300 to 600 mg every 21 or 28 days in a run-in period of 2 to 6 administrations, aiming at keeping the IgG trough levels above 5 g/L. In the one-year test period, the patients will receive the test IVIG at the same dose/intervals of the optimization. However, the IgG trough levels will be monitored every visit, and new adjustments/dose optimization will be performed whenever needed to keep the IgG trough levels above 5g/L. | Biological: IVIG<br>* Patients with primary immunodeficiency will switch to Shu Yang IVIG and optimize the posology to IgG 300 to 600 mg every 21 or 28 days in a run-in period of 2 to 6 administrations, aiming at keeping the IgG trough levels above 5 g/L. At Visit 4, at least 20 patients will perform the PK assessment, collecting additional blood samples.<br>* Other names: Shu Yang IVIG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Efficacy Objective (average of acute serious bacterial infections) | The incidence of serious bacterial infections (septicemia, meningitis, visceral abscess, osteomyelitis, and pneumonia) within the 1-year follow-up is less than 1.0 per patient/year in the average of the population. | Between Visit 0 and Final Visit (through study completion, an average of 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Efficacy Objectives (assessment of the rate of non-serious infections) | The incidence of all acute infections except the serious acute bacterial infections within the 1-year follow-up (simple descriptive statistics). | Average incidence of non-serious infections per patient between Visit 0 and Final Visit (through study completion, an average of 1 year), as documented as treatment emergent adverse events (TEAEs); | 
| Secondary Efficacy Objectives | Assessment of treatment length of infections per year; | Average number of days for treating infections per patient between visit 0 and final visit (through study completion, an average of 1 year), as documented as treatment emergent adverse events (TEAEs); | 
| Secondary Efficacy Objectives | Assessment of missing time from school/work due to infections per month; | Average number of days off from school/work per patient/month, as documented in the patient's diary (through study completion, an average of 1 year); | 
| Secondary Efficacy Objectives | Assessment of hospitalization episodes and length. | Number of days hospitalized per month overall and due to infection, as documented as treatment emergent adverse events - TEAEs (through study completion, an average of 1 year). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IVIG, IMUNOFORTE, PID