Clinical trial NCT06954441: V-IMMUNE: A Novel Immunoglobulin Therapy for Immunodeficiency
Official title: V-IMMUNE® for Primary Immunodeficiency: A Phase III Clinical Trial (VIP Study)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Immunodeficiencies
Primary Immunodeficiencies (PID)
Agammaglobulinemia
Keywords: immunodeficiency
intravenous immunoglobulin
pharmacokinetics
safety
efficacy
serious bacterial infection
temporally related adverse event
Lead sponsor: On Pharma Importadora, Exportadora e Distribuidora de Medicamentos LTDA.
Sponsor class: OTHER
Collaborators: name: Hospital do Coracao
First posted: 2025-05-01
Enrollment: 50
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All participants will get the same intervention: IV immunoglobulin each 3 weeks. Participants meeting the inclusion criteria will receive V-IMMUNE® at a dose of 600 mg/kg, with infusion rates progressively increased to a maximum of 0.06 mL/kg/min, provided no adverse events occur. Pre-medication with intravenous normal saline, hydrocortisone and diphenhydramine is administered to mitigate infusion-related risks.
Primary purpose: TREATMENT

Brief summary: This is a phase III, non-randomized clinical trial (VIP Study) designed to assess the safety and efficacy of V-IMMUNE®, a 5% human normal immunoglobulin preparation, in approximately 50 patients with primary immunodeficiency (PID). Participants, all aged ≥2 years and already receiving IVIG therapy, will be switched to V-IMMUNE® at a dose of 600 mg/kg every three weeks via intravenous infusion. The study will use historical data as a control and extend over 12 months, with scheduled visits at each infusion (an estimated 17 infusions per participant).

Objectives and Outcomes Primary Efficacy Endpoint: Rate of serious bacterial infections over 12 months. Primary Safety Endpoint: Proportion of infusions with one or more temporally associated adverse events (AEs).

Secondary Endpoints: Additional safety outcomes (e.g., average number of AEs within 72 hours per infusion), efficacy measures (non-serious bacterial infections, time to resolution, antibiotic use, hospitalizations), and quality of life (SF-36) at 6 and 12 months. A pharmacokinetic (PK) sub-study will be conducted in 20 participants aged ≥16 years to evaluate total IgG levels, half-life, AUC, Cmax, and other PK parameters.

Study Design and Intervention V-IMMUNE® is given at an initial infusion rate of 0.01 mL/kg/min for 30 minutes, increasing stepwise up to 0.06 mL/kg/min if well tolerated. Pre-medication, including rapid IV saline, diphenhydramine, and hydrocortisone, will be administered for the first three months to reduce the risk of infusion-related AEs. Patients at elevated thromboembolic risk will receive the lowest feasible infusion rate.

Sample Size and Analysis Fifty patients will be enrolled to ensure adequate power to demonstrate a severe infection rate below one event per person-year (with a one-sided 1% significance level). Safety endpoints will be met if the upper bound of the 95% confidence interval for the proportion of temporally associated infusion-related AEs remains below 40%, assuming a true rate under 20%. An interim analysis is planned at six months or upon reaching 50% enrollment.

Detailed description: Introduction:

Immunoglobulin is used as a treatment for a variety of medical conditions, not only for its ability to combat infection as replacement therapy, but also for its anti-inflammatory and immunomodulatory effects. Immunoglobulins are primarily characterized by their antibody function, with various classes and subclasses that perform different roles. B cells are primarily responsible for the humoral adaptive immune response (antibody-mediated). Immunoglobulins, which are the molecules with antibody function, serve as the receptors of B cells, anchored to the membrane via a molecular complex composed of molecules that both anchor the immunoglobulin and promote signal transduction into the cell. This enables B cell activation, triggering a signaling cascade that leads to terminal differentiation into plasma cells or memory cells.

Inborn errors of immunity (primary immunodeficiencies - PIDs) represent a large, heterogeneous, and rapidly growing group of genetic diseases, primarily (but not exclusively) caused by loss- or gain-of-function germline mutations in genes associated with the immune response. Despite their individual rarity, inborn errors collectively affect a significant proportion of patients, with an estimated global prevalence of 1 in 1,200-2,000. They now comprise approximately 500 known genetic causes, subdivided into 10 categories listed in the 2022 classification by the International Union of Immunological Societies (IUIS), about two-thirds of which have been identified in the past decade. As evidence of the field's dynamic development, approximately 30 new diseases have been described per year in recent years.

Worldwide, the most common defects among PIDs-approximately 60%-involve impaired antibody production, with selective IgA deficiency and common variable immunodeficiency being the most prevalent. At least 80% of patients diagnosed with antibody deficiency receive IgG replacement therapy. PIDs can be an unrecognized underlying condition associated with autoimmune, allergic, and lymphoproliferative diseases and may therefore remain undiagnosed for many years. Patients diagnosed with B cell dysfunction and resulting antibody deficiencies require immunoglobulin G (IgG) replacement, a safe and effective therapeutic option for preventing infections in patients with PIDs.

Intravenous immunoglobin is used to treat a wide range of diseases. However, its approved indications can be divided into three main categories: primary and secondary antibody deficiencies, vertically transmitted HIV, chronic lymphocytic leukemia (CLL), immune thrombocytopenic purpura (ITP), chronic inflammatory demyelinating polyneuropathy (CIDP), severe disseminated infections, and graft-versus-host disease. It is recommended to initiate immunoglobulin replacement therapy in all patients who meet the diagnostic criteria for IgG hypogammaglobulinemia, whether they have agammaglobulinemia, common variable immunodeficiency (CVID), or IgG subclass deficiencies with functional antibody production impairment In this protocol, investigators discuss the use of a commercially available human polyvalent immunoglobulin product for intravenous use at 5% concentration, branded V-MMUNE, for the treatment of inborn errors of humoral immunity / primary immunodeficiencies involving impaired production of IgG class immunoglobulins by B lymphocytes.

Considering the relative unavailability of blood products, among which immunoglobulins are in the most critical category, the approval of new products in Brazil is of utmost importance due to the increasing need for this medication-even for well-defined indications such as hypogammaglobulinemia, whether primary or secondary, as well as neuropathies like Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and hematologic conditions such as immune thrombocytopenic purpura. Several factors have contributed to this shortage, including increasingly stringent safety requirements; the difficulty in obtaining high-quality plasma that meets the standards of major regulatory agencies such as the FDA and EMA; the need to improve manufacturing processes; the reduction in the number of donors due to the COVID-19 pandemic; and the increased demand for IVIG at the beginning of the pandemic, when immunoglobulin was used as a therapeutic attempt for a then-unknown disease.

Therefore, the availability of new products, like V-IMMUNE produced by Virchow Laboratories in India, that are effective for the treatment of clearly defined indications and possess the necessary safety profile-ensuring minimal adverse reactions during and after clinical use-is essential.

The investigators present here a clinical trial for regulatory approval of a novel immunogloblin V-IMMUNE® in the Brazilian market for primary immunodeficiency.

Objectives

The objectives of the study are:

1. To evaluate the efficacy of the human normal immunoglobulin preparation V-IMMUNE® for patients with primary humoral immunodeficiency in preventing the rate of serious bacterial infection in 12 months compared to historical controls;
2. To evaluate the safety of the human normal immunoglobulin preparation V-IMMUNE® regarding the observed proportion of infusions with one or more temporally associated adverse events in patients with primary humoral immunodeficiency;
3. To evaluate the pharmacokinetics of intravenous V-IMMUNE® in patients with primary humoral immunodeficiency.

   Methods:

   Study Design This is a prospective, Phase III, open-label, non-randomized, multicenter, single-group study with a historical control for the regular administration of V-IMMUNE® via the intravenous route.

   Recruitment Plan Recruitment will take place through 10 national reference immunology centers specialized in the treatment of primary immunodeficiency with intravenous immunoglobulin infusion. Patients who are already receiving regular intravenous immunoglobulin therapy and meet the eligibility criteria will be invited to participate in the study, switching from their current product to the investigational product (IP) for a duration of 12 months.

   Recruitment Approach Patients who meet the inclusion criteria and are already receiving IgG treatment at the participating centers will be approached for inclusion in the VIP study. Once the informed consent form (ICF) is signed, the participant will begin receiving V-Immune® (On-Pharma) as per the study protocol.

   As this is a single-group study, randomization will not be performed. Blinding Given that this is a single-group study and the eligible patients are already being treated with another commercially available immunoglobulin, which will be replaced by V-IMMUNE®, blinding is deemed unnecessary.

   Experimental Intervention The Investigational Product (IP) is V-IMMUNE®, normal human immunoglobulin I.P. 5% (5g/100 mL), manufactured from qualified human plasma for intravenous use. Each vial contains Human Immunoglobulin 50 g/L, Maltose 100 g/L, and Water for Injection. The 5% Human Immunoglobulin solution for intravenous administration I.P. is a sterile, pyrogen-free preparation of normal human immunoglobulin in a single-dose form for intravenous infusion. Each 10 mL, 50 mL, and 100 mL contains 0.5 g, 2.5 g, and 5 g of normal human immunoglobulin, respectively, and is prepared from qualified human plasma using membrane filtration, combined chromatographic steps, and viral inactivation procedures. The IgA content does not exceed 2 mg/mL. The IgG subclass distribution is similar to that found in normal human serum.

   The manufacturing process uses plasma collected from donors who are screened based on medical history, in accordance with regulatory authority guidelines. The blood is tested for mandatory infectious diseases. Only plasma that tests negative for HBsAg, HCV, and HIV antibodies is used in the process.

   Normal Human Immunoglobulin I.P. 5% (5g/100 mL) V-IMMUNE® will be administered at a dose of 600 mg/kg every 3 weeks (+/- 3 days) via intravenous (IV) route at the infusion rate specified below, over a duration of 3 to 6 hours:

   0.01 ml/kg/min 0-30 min, 0.02 ml/kg/min 31 to 45 min, 0.04 ml/kg/min 46 to 60 min and 0.06 ml/kg/min 61 min until the end of infusion.

   Dose Escalation Dose escalation occurs gradually unless adverse events (AEs) occur. The dose is only increased if there is good tolerance, without the presence of adverse events. If an AE occurs, the infusion must be paused for 20 to 30 minutes. The use of loratadine, paracetamol, and ondansetron will be allowed. Exceptionally, another drug from the same class may be used, provided the pharmacokinetics study center is informed. Once the patient improves, the infusion is resumed at a reduced rate, returning to the initial infusion speed. The patient will be observed for 60 minutes after the infusion ends for clinical assessment and monitoring of potential adverse events .

   Pre-medication Pre-medication prior to infusion of the investigational product: rapid infusion of 500 mL of 0.9% sodium chloride (NaCl) IV, diphenhydramine 50 mg IV, and hydrocortisone 200 mg IV, followed by the investigational product administered at progressively increasing infusion rates as described above. After infusion, 0.9% NaCl should be continued at 1 mL/kg/hour. The use of pre-medication is standard medical practice and is considered necessary for participant safety.

   Rapid isotonic saline infusion before administration and slow isotonic saline infusion to maintain venous access for at least 30 to 40 minutes are necessary and standard practice in the administration of these blood products. Rapid crystalloid before infusion reduces the risk of headaches and aseptic meningitis post-administration, as well as the risk of thromboembolic events. Crystalloid administration after the investigational product infusion reduces the risk of serious and potentially life-threatening adverse events due to anaphylactic reactions by allowing for the rapid administration of IV medications in a potentially shocked patient, avoiding the need for emergency central venous access.

   Pre-medication Summary:

   Rapid infusion of 500 mL of 0.9% sodium chloride (NaCl) IV

   Diphenhydramine\* 50 mg IV (adult); Pediatric: 1.25 mg/kg IV

   Hydrocortisone\*\* 200 mg IV (adult); Pediatric: 3 mg/kg IV

   After infusion: 0.9% NaCl at 1 mL/kg/hour for one hour

   Thromboembolism risk: use the slowest possible infusion rate

   \* Administer 30 minutes before infusion.

   \*\* Administer 30 minutes to 1 hour before infusion.

   For individuals at risk of thromboembolism, the infusion rate must be kept as low as possible.

   Thromboembolism risk factors include: advanced age, obesity, hypertension, diabetes mellitus, history of previous thromboembolic events, known acquired or congenital thrombophilic disorders, prolonged immobilization, severe hypovolemia, or increased blood viscosity.

   Treatment intervals between administrations should remain constant throughout the study, provided that the IgG trough levels remain \>500 mg/L.

   If body weight changes by more than 5% compared to baseline (screening visit), the dose will be adjusted to maintain a consistent mg/kg body weight dosage.

   In the event of clinically significant hypotension and/or anaphylactic reactions, in addition to stopping the infusion and administering appropriate supportive care (which may include epinephrine, antihistamines, corticosteroids, supplemental oxygen, and volume expansion), and recording the incident in the CRF as an AE, the participant may be withdrawn from the study at the investigator's discretion. In such cases, participants may, if they wish, complete follow-up visits

   Contraindications and Precautions Related to the IP Normal Human Immunoglobulin for Intravenous Administration I.P. 5% is contraindicated in patients with selective IgA deficiency.

   Patients may experience severe hypersensitivity reactions or anaphylaxis in the presence of detectable IgA levels after infusion of Normal Human Immunoglobulin I.P. 5%. The occurrence of severe hypersensitivity reactions or anaphylaxis under such conditions should prompt consideration of alternative therapy.

   The intravenous solution of Normal Human Immunoglobulin should only be administered intravenously.

   Additional listed precautions regarding the use of Normal Human Immunoglobulin I.P. 5% include:

   Hypersensitivity: Immediate hypersensitivity and anaphylactic reactions are rare but possible. If hypersensitivity occurs, immediately stop the infusion and initiate appropriate treatment. Medications such as epinephrine and antihistamines should be readily available for the immediate treatment of acute hypersensitivity reactions, including anaphylaxis.

   Renal dysfunction: Acute renal failure, osmotic nephropathy, and death may occur with IVIG use. Ensure that the patient is not hypovolemic prior to administration. In patients at risk of renal dysfunction due to pre-existing renal insufficiency or predisposition to acute renal failure (e.g., diabetes mellitus, hypovolemia, obesity, use of nephrotoxic medications, or age \>65), IVIG should be administered at the minimum infusion rate.

   Aseptic Meningitis Syndrome (AMS): Rarely occurs with IVIG treatment. May begin within hours to 2 days after treatment. Discontinuation of IVIG usually leads to full recovery without sequelae. More common with high doses (2 g/kg) and/or rapid infusion.

   Hemolysis: IVIG products may contain blood group antibodies that act as hemolysins, coating red blood cells and causing a positive direct antiglobulin test and, rarely, hemolysis. Delayed hemolytic anemia may occur due to red cell sequestration and acute hemolysis, consistent with intravascular hemolysis.

   Transfusion-Related Acute Lung Injury (TRALI): Non-cardiogenic pulmonary edema may occur after IVIG administration. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever, typically occurring 1 to 6 hours post-treatment. Patients should be monitored for pulmonary adverse events. If TRALI is suspected, appropriate tests should be conducted for anti-neutrophil antibodies in both the product and patient serum. Treatment includes oxygen therapy and ventilatory support.

   Transmissible Agents: Normal Human Immunoglobulin I.P. 5% is derived from human plasma. Due to effective donor screening and manufacturing processes, the risk of viral disease transmission is extremely low. The theoretical risk of Creutzfeldt-Jakob disease (CJD) transmission is also considered extremely remote.

   Monitoring - Laboratory Tests: Periodic monitoring of renal function and urine output is crucial in patients at increased risk of acute renal failure. Renal function (including serum urea and creatinine levels) should be assessed before the initial infusion and periodically as per the visit schedule. Due to a potentially increased risk of thrombosis, baseline blood viscosity assessment should be considered in patients at risk of hyperviscosity, including those with cryoglobulinemia, fasting chylomicronemia/markedly elevated triglycerides, or monoclonal gammopathies. If signs/symptoms of hemolysis are observed post-infusion, appropriate lab tests should be conducted. In cases of suspected TRALI, tests for anti-neutrophil antibodies should be performed on the product and patient serum.

   Patient Information: Patients should be instructed to immediately report symptoms such as decreased urine output, sudden weight gain, fluid retention, edema, and/or shortness of breath-which may indicate kidney injury.

   Pregnancy - Category C: Reproduction studies in animals have not been conducted with Normal Human Immunoglobulin for IV use. It is also unknown whether it can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. It should be used during pregnancy only if absolutely necessary. Pregnant women are part of this study's exclusion criteria.

   Presentation of the Investigational Product (IP) Normal human immunoglobulin for intravenous administration I.P. 5%, V-IMMUNE®, is available in vials of 0.5g/10 mL, 2.5g/50 mL, and 5g/100 mL (5% concentration), in single-dose format for intravenous administration.

   IP Manufacturing and Labeling V-IMMUNE® immunoglobulin is manufactured, packaged, and labeled by Virchow Biotech Private Limited, and imported by OnPharma Importadora Exportadora e Distribuidora de Medicamentos LTDA, in accordance with current regulations. The preparation and labeling of the IP follow Good Manufacturing Practice (GMP) guidelines, and its distribution adheres to Good Distribution Practice (GDP) guidelines. IP labels will be in Portuguese and meet Brazilian legal requirements.

   Storage and Use Conditions of the IP V-IMMUNE® immunoglobulin must be stored in a secure area with limited access, preferably in a locked cabinet, protected from light, and kept at a temperature between 2°C and 8°C. V-IMMUNE® must not be frozen.

   Patient Confinement Procedures Patients not selected for pharmacokinetic (PK) analysis must arrive at the study centers 60 minutes before infusion and remain under observation for 60 minutes after the infusion ends for clinical assessment and monitoring for adverse events.

   For patients selected/eligible for PK analysis, the same confinement period will apply on infusion days 1 to 8 and 10 to 17. However, on day 9, these patients must arrive 60 minutes before the infusion and remain at the center for up to 6 hours after the infusion for blood sample collection. They must also return for blood draws at 24 hours, 72 hours, 7 days, 14 days, and 21 days after the 9th infusion.

   Pharmacokinetic Parameters

   The following pharmacokinetic parameters will be determined for this study:

   Cmax: Maximum plasma concentration reached, based on experimental data obtained directly from the plasma concentration-time curve.

   AUC₀-t (Area Under the Curve): Area under the plasma concentration-time curve from time zero to the last concentration above the lower limit of quantification, calculated using the trapezoidal rule.

   AUCinf: Area under the plasma concentration-time curve from time zero to infinity (extrapolated), calculated as AUCinf = AUC₀-t + Ct/Kel, where Ct is the last measurable concentration and Kel is the elimination rate constant.

   Tmax: Time to reach Cmax. Kel: Elimination rate constant, estimated from the slope of the linear regression of the natural logarithm of concentration versus time for at least three data points above the lower limit of quantification.

   T½ (Half-life): Elimination half-life, calculated as ln(2)/Kel. Vd (Volume of distribution): Volume of distribution from the terminal phase of the pharmacokinetic curve, calculated as Dose/(Kel × AUCinf).

   Sampling Schedule Samples will be collected using 7.5 mL tubes with gel separators, labeled with participant number, collection number, timepoint, infusion number, product code (IGG), and protocol number. Blood samples of 7.5 mL each will be collected before infusion number 0 (prior IVIG treatment used by the participant) and before infusions 1 to 9 of V-IMMUNE®.Post-infusion pharmacokinetic samples will be collected following the ninth (9th) infusion Analytical Stage According to the literature, the analytical phase involves a sample preparation method based on enzymatic digestion with trypsin. This may be preceded by reduction and/or alkylation followed by enzymatic digestion.

   The cited preparation approach aims to develop and apply a robust and selective MRM (Multiple Reaction Monitoring) method, capable of detecting a specific Q1/Q3 ion pair derived from the digestion of the target protein-in this case, IgG-thus indirectly determining its plasma concentration. Given the existence of multiple IgG subclasses (IgG1, IgG2, IgG3, and IgG4), specific peptide fragments can be found in protein databases and scientific literature that are unique to each subclass. The following peptide sequences have been adopted as the starting point for the development of the bioanalytical method for quantifying total IgG and its subclasses:

   Peptide FNWYVDGVEVHNAK - specific for IgG1 Peptide CCVECPPCPAPPVAGPSVFLFPPKPK - specific for IgG2 Peptide WYVDGVEVHNAK - specific for IgG3 Peptide TTPPVLDSDGSFFLYSR - specific for IgG4 Since the analyte is an endogenous substance, a bioanalytical method using a surrogate matrix (in this case, bovine plasma) is necessary. This surrogate will be used to generate calibration curves and quality control samples processed in a similar manner to the unknown samples from study participants.

   For sample preparation and LC-MS/MS analysis, the following reagents may be used if extraction with prior reduction and alkylation is required: ammonium bicarbonate, 2,2,2-trifluoroethanol, DL-dithiothreitol, iodoacetamide, formic acid or acetic acid, among others. If only protein precipitation followed by enzymatic digestion is performed, reagents such as acetone, isopropanol, perchloric acid, acetonitrile, or methanol may be used.

   In both cases, the sample must be incubated with MS-grade trypsin at a minimum suggested concentration of 1 g/L.

   Chromatographic methods will employ mobile phase gradients to improve separation of the various peptide chains that may be formed during extraction. The system will operate at pressures compatible with UPLC, with an aqueous mobile phase containing 0.1% formic acid and an organic phase consisting of methanol or acetonitrile, also with 0.1% formic acid. Recommended columns include solid-core types such as Waters X-Bridge C8 (3.0 × 30 mm, 3.5 µm) or Agilent Eclipse Plus C18 RRHD (1.8 μm, 2.1 × 100 mm).

   Detection of the analytes will be performed using a triple quadrupole mass spectrometer, model API6500 from Sciex. The method will be validated in accordance with RDC No. 27, dated May 17, 2012, covering the validation parameters of linearity, precision, accuracy, carryover, matrix effect, selectivity, stability in biological matrix, and solution stability Control or Standard Treatment: The control group will consist of historical controls as described in the literature Co-interventions: No co-interventions will be allowed. Follow-up For 12 months.

   Visits:

   • All immunoglobulin infusion opportunities with data collection - it is anticipated that there will be 17 visits for V-IMMUNE® infusion during 1 year. Patients will be observed:
   * Immediately before infusion;
   * During infusion and up to 60 minutes after;
   * 24 and 72 hours after the start of infusion of the investigational product - by telephone contact.

   Laboratory data:

   At "Baseline", and before performing 1st, 3rd, 6th, 9th, 12th, and 17th infusions:

1. BHCg, CBC, platelets, electrolytes, serum glucose, urea, creatinine, AST, ALT, LDH, total and partial urine bilirubin (type 1)

Before performing 1st, 3rd, 6th, 9th, 12th, and 17th infusions:

1. Haptoglobin, Coombs

Before all infusions:

1. Trough IgG Screening Visits (T1 and T2)

Objective:

Identify eligible patients by evaluating inclusion and exclusion criteria, measuring IgG levels, and obtaining informed consent.

Activities at Screening Visit T1: Reception and Informed Consent:

Provide a detailed explanation of the study, including objectives, procedures, risks, and benefits.Written informed consent (ICF/Assent) must be obtained by qualified and delegated personnel and signed by the investigator before any study procedures or screening labs are conducted.

Assess time since primary immunodeficiency diagnosis. Assess premedication use with prior IgG infusion. Check osmolarity and IgA content of previous IgG. Assess adherence to previous IgG treatment (infusion frequency and two most recent trough levels).

Obtain written informed consent.

Demographic and Medical History Data Collection:

Record age, sex, race, weight, and BMI. Collect medical history, including infections and current medications.

Eligibility Criteria Assessment:

Review inclusion criteria (e.g., confirmed diagnosis, appropriate age). Evaluate exclusion criteria (e.g., autoimmune disease, IgG allergy).

Physical and Clinical Examination:

Perform a physical exam. Record vital signs (RR, HR, BP, temperature).

Sample Collection for Lab Tests:

Baseline IgG levels:

If two prior IgG levels \>500 mg/dL within 90 days, patient may proceed without new screening lab.

If one prior IgG level \>500 mg/dL within 30 days, proceed to T2 for second test.

If IgG at T1 \>700 mg/dL, infusion may proceed at T2 even before T2 result. Other labs per protocol. Quality of Life and Symptom Questionnaires:Apply SF-36 QoL questionnaire. Assess current symptoms related to the condition.

Activities at Screening Visit T2:

Reassess IgG treatment adherence. echeck inclusion/exclusion criteria. Repeat physical exam and vitals. Collect second IgG sample if needed (may occur same day as first infusion if prior level \>700 mg/dL).

Other protocol-specific labs. Flexible window: Screening can be extended (investigator's discretion) until baseline IgG \>500 mg/dL is confirmed.

First Infusion Visit (I1) Objective: Confirm eligibility and start IP administration.

Activities:Review Screening Results:

Review lab findings and eligibility criteria. Discuss abnormal results and eligibility status.

Clinical Assessment:

Update physical exam and vital signs. Review health status changes. Provide symptom diary instructions.

Eligibility Confirmation:

Final eligibility confirmation. Review concomitant medications.

Lab Sample Collection:

Baseline IgG. Pregnancy test for women of childbearing age unless permanently sterile. Other tests: CBC with platelets, electrolytes, glucose, urea, creatinine, AST, ALT, LDH, urinalysis, pneumococcal and Haemophilus antibody titers.

Pre-dose IgG from prior product. Pre-dose PK samples.

First Infusion of V-Immune®:

Explain procedure. Record batch number and expiration date. Administer per infusion protocol.

Monitor for adverse events (AEs):

Record AE, infusion rate at onset, interruptions, restart rate, total infusion time, total IgG dose, and premedication use.

Post-Infusion Data Collection:

Record AEs, post-infusion vitals (30-60 min), and general condition. Record discharge time.

Patient Instructions:

Provide post-infusion guidance, emergency instructions, and team contact. Inform that follow-up calls will occur at 24 and 72 hours. Schedule next visit. Infusions 2 to 16 (I2 to I16) Objective: Conduct infusions every 3 weeks (±3 days).

Activities:

Review Previous Results and Clinical Status:

Review previous labs and symptoms. Update physical exam and vitals. Review infections, hospitalizations, antibiotics, time to resolution, and workdays lost.

SF-36 at infusions 8 and 16.

Lab Collection:

Pre-infusion IgG for all visits. Pre-dose PK samples for infusions 1-9. Total 12 PK samples per adult; children only pre-dose. Infuions 3, 6, 9, 12, 17: pregnancy test for women of childbearing potential. Other labs: CBC, electrolytes, glucose, urea, creatinine, AST, ALT, LDH, urinalysis, haptoglobin, Coombs test.

\*Infusion 6: pneumococcal and Haemophilus antibody titers.

V-Immune® Infusion:

Record batch and expiration. Administer per protocol. Monitor and document AEs and all infusion details.

Post-Infusion:

Record AEs, post-infusion vitals (30-60 min), discharge time, PK per section

Patient Instructions:

Post-infusion guidance, team contact, 24h/72h follow-up calls, next visit scheduling.

Physical Examination

Conducted by qualified staff, includes:

General appearance, head/ENT, thorax, cardiovascular, respiratory, abdomen, musculoskeletal, genitourinary, skin.

Clinically significant changes are recorded as AEs. Vital Signs

To be consistently collected in the same position:

Systolic/diastolic BP, HR (bpm), RR (breaths/min), temperature (°C). Final Infusion and End-of-Study Visit

Activities:

Severe Infections per Patient-Year:

Total number, type, treatment, and outcomes.

Infusions with AEs:

Total infusions vs. number with AEs.

Safety and AE Assessment:

Infusion-related AEs: severity, duration, outcome, causality. Serious AEs (SAEs): details, actions, outcomes.

Overall Clinical Assessment:

Complete physical exam, vital signs.

Quality of Life:

SF-36, patient satisfaction.

Treatment Adherence:

Confirm monthly infusions, missed/delayed doses, reasons.

Final Participant Debriefing:

Summary of treatment, post-study follow-up plans.

Final Visit Procedures:

Check-in, contact updates, document AEs, discuss outcomes and study closure. Strategies to Minimize Loss to Follow-Up Missed Visits and Scheduled Sample Deviations Reschedule within 7 days. Mark as "missed/unavailable" if patient cannot attend.Only classified as loss to follow-up if no contact is possible by study end despite all efforts.

Patient Withdrawal from the Study

Occurs if:

Requested by patient. Two consecutive or three total missed visits. Development of HBV, HCV, or HIV. SAE making further IP dosing inappropriate (investigator discretion). Use of exclusionary medications Withdrawal of Consent A participant will be considered to have "Withdrawn Consent" if they choose to discontinue participation in any further study procedures. This right will be acknowledged and confirmed through the Informed Consent Form (ICF/Assent Form). Once consent is withdrawn, no additional study procedures will be carried out and no further data will be collected. Data collected up to the point of withdrawal will remain in the study database; however, if the participant requests the removal of their data, it will not be used.

Sample size calculation and statistical analysis plan. The investigators will include 50 patients to meet the sample size required to evaluate efficacy

Safety:

41 participants with at least complete data provides with a 90% probability of finding an upper limit of the one-sided 95% confidence interval \< 0.40, assuming that the true observed proportion of infusions with one or more temporally associated AE is less than 20%. National data corroborate the above premise

Efficacy:

50 participants are required. Assuming a serious infection rate per person-year \< 1, the investigators will have a 90% power to reject the one-sided H0 that the serious infection rate ≥ 1 per person-year, with a 1% significance level and 20% loss to follow-up. This number is compatible with the FDA rule that suggests that the upper limit of the 99% confidence interval should be \< 1 serious infection per person-year. The investigators plan an interim analysis after 6 months of treatment or when 50% of the sample is reached, whichever occurs first, with a significance level of 0.5%, based on the Pocock criterion , to maintain an overall significance level of 1%.

Pharmacokinetics:

Number of patients per age group follows EMA recommendations. There will be 20 adult or adolescent participants aged 16 years or older. As recommended by the EMA, trough values will be collected for children, but without a complete pharmacokinetic curve in order to reduce the burden of multiple blood collections for this age group. Participants are the same as those in the efficacy and safety study.

Eligibility criteria: Inclusion Criteria:

* Patients aged 2 years or older;
* Primary immunoglobulin G deficiency, already receiving another intravenous immunoglobulin (IVIG). Primary IgG deficiency may be secondary (non-exhaustive list) to one of the following diagnoses:
* Agammaglobulinemia due to absence of B cells
* Hypogammaglobulinemia with reduced antibody function - variable common immunodeficiency complex
* Quantitative and functional deficiencies of immunoglobulin G
* Normal immunoglobulin with reduced capacity for antibody production after immunization (e.g., Wiskott-Aldrich syndrome, IgG subclass 2/4 deficiency, antipolysaccharide antibody deficiency against Haemophilus or pneumococcus)
* Severe combined immunodeficiencies: DiGeorge syndrome presenting with immunoglobulin G deficiency
* Isotype-switching defects: hyperimmunoglobulinemia M syndromes
* Two trough IgG measurements ≥500 mg/dL within the past 90 days.

Exclusion Criteria:

* Acute infection under treatment within 2 weeks prior to screening
* Pregnancy
* History of hypersensitivity reaction to blood or blood products
* Previous anaphylactic reaction to IgG
* Intolerance to any component of V-Immune
* IgA deficiency, history of reactions to products containing IgA, or history of anti-IgA antibodies
* Deficiency of IgA, IgM, IgD, or IgE
* Participation in any other study involving an investigational product
* Exposure to blood or any blood-derived products in the last 3 months
* Known HIV, HCV, or HBV infection
* ALT \>3× the upper limit of normal
* Serum creatinine \>2× the upper limit of normal
* BUN \>2.5× the upper limit of normal
* History of NYHA class III/IV heart failure
* Uncontrolled hypertension with systolic BP \>160 mmHg or diastolic BP \>100 mmHg
* History of thrombotic events such as DVT, MI, stroke, or PE within the last 6 months
* Neoplasia under treatment
* Severe hepatic, renal, or cardiac insufficiency
* Child-Pugh class B/C hepatic insufficiency
* Alcohol, opioid, or psychotropic drug abuse within the last 12 months
* Use of immunosuppressive agents
* Long-term use of prednisone \>10 mg/day or equivalent
* Protein-losing enteropathies (Crohn's disease, ulcerative colitis, Ménétrier's disease, celiac disease)

Primary outcomes:
measure: Efficacy primary outcome
timeFrame: 12 months
measure: Safety outcome
timeFrame: 72 hours
Secondary outcomes:
measure: Severe and non-severe bacterial infections
timeFrame: 12 months
measure: Number of patients with 0, 1, 2, etc., severe infections
timeFrame: 12 months
measure: Number of adverse events by body systems
timeFrame: 12 months
measure: Time to first infection
timeFrame: 12 months
measure: Nadir of pre-infusion total IgG level
timeFrame: 3 weeks
measure: Nadir of pre-infusion total IgG level in children aged 2 to <16 years
timeFrame: 3 weeks after the fifth infusion
measure: Number of any severe or non-severe infection
timeFrame: 12 months
measure: Infection resolution time
timeFrame: 12 months
measure: Use of antibiotics
timeFrame: 12 months
measure: Hospitalizations due to infections
timeFrame: 12 months
measure: Episodes of fever
timeFrame: 12 months
measure: Number of days absent from school or work
timeFrame: 12 months
measure: Quality of life: Short Form Health Survey (36)
timeFrame: 6 and 12 months
measure: Minimum total IgG level (500 mg/dL) not reached
timeFrame: 12 months
measure: Trough total IgG measurement
timeFrame: 12 months
measure: Secondary safety outcome
timeFrame: 12 months
measure: Secondary safety outcome
timeFrame: 12 months
measure: Secondary safety outcome
timeFrame: 12 months
Other outcomes:
measure: Cmax
timeFrame: 12 months
measure: ASC0-t
timeFrame: 12 months
measure: Tmax
timeFrame: 12 months
measure: Kel
timeFrame: 12 months
measure: T1/2
timeFrame: 12 months
measure: Vd
timeFrame: 12 months
Locations:
Study officials:
affiliation: Hospital do Coracao
name: Israel Silva Maia, PhD
role: STUDY_CHAIR
affiliation: Hospital do Coracao
name: Dewton Moraes Vasconcelos, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: FDA. 2008. Guidance for Industry: Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency
citation: Goudouris ES, Silva AMDR, Ouricuri AL, Grumach AS, Condino-Neto A, Costa-Carvalho BT, Prando CCM, Kokron CM, Vasconcelos DM, Tavares FS, Segundo GRS, Barreto ICDP, Dorna MB, Barros MAMT, Forte WCN. Comment to: II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies. einstein (Sao Paulo). 2017;15(1):1-16. Einstein (Sao Paulo). 2017 Oct-Dec;15(4):522. doi: 10.1590/S1679-45082017CE4250. No abstract available.
citation: Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med. 1991 Jul 11;325(2):110-7. doi: 10.1056/NEJM199107113250207. No abstract available.