IVIG Boya: Safety, Efficacy, and Pharmacokinetics

Evaluating the Safety, Effectiveness, and Pharmacokinetics of Boya Intravenous Immune Globulin in Patients With Primary Immune Deficiency.

The goal of this phase 3, open-label, single-group clinical trial is to assess the efficacy of Boya IVIG in maintaining the mean number of serious bacterial infections to less than one per year in participants with primary immunodeficiency (PYD) due to common variable immunodeficiency (CVID), as defined by the European Immunodeficiency Society (ESCID) / Pan American Immunodeficiency Group (PAGID), or X-linked agammaglobulinemia (XLA), as defined by molecular genetic testing (ESCID/PAGID).

The safety and pharmacokinetics (PK) of the investigational product will also be evaluated.

Participants must:

• Visit the research center every 21 or 28 days to receive the experimental product infusion and undergo a medical examination.
• During weekly telephone calls, report, if applicable, adverse events and hospitalizations; the number of school or workdays missed due to infections; the length of hospital stay; and the use of antibiotics for therapeutic purposes.

Fifty male or female participants aged 2 to 60 years, either treatment-naive or already receiving intravenous immunoglobulin replacement therapy, will be enrolled, including at least 20 participants aged 2 to 17 years. The study will also examine the pharmacokinetic (PK) profile in adult participants.

After obtaining signed informed consent or assent, screening will include reviewing immunodeficiency history in medical records, performing safety examinations, and assessing eligibility against inclusion and exclusion criteria.

Subjects who pass screening will begin a 6-visit run-in period. For participants already receiving treatment, the interval between intravenous injections should remain as prescribed before enrollment unless modified during the run-in period. During this period, participants will receive the study IVIG. For treatment-naïve participants, the dose and administration interval during the run-in will be determined by the Investigator.

After the run-in, the one-year trial will begin at V0. Study visits will be scheduled every 21 or 28 days, based on the participant's prescribed treatment plan. Each visit will have a ±3-day window around the scheduled date. At each visit, blood samples will be collected immediately before each IVIG dose to measure IgG trough levels. If a visit occurs earlier or later than the scheduled date, whether within or outside the allowed window, the timing of the next visit will be based on the actual date of the previous visit to maintain consistent planned inter-visit intervals throughout the study.

The V0 assessment will begin when participants have IgG concentrations ≥5 g/L on two consecutive infusions under the same dosing conditions. Therefore, the run-in period may include only two visits. If, among the six visits, the trough IgG concentration does not reach 5 g/L on two consecutive visits, the participant will be considered to have failed screening but may be rescreened.

To characterize the pharmacokinetic (PK) profile of the investigational product, at least 20 adult participants will undergo additional blood sampling between two consecutive study visits to measure total IgG concentrations and antigen-specific antibody levels, including anti-pneumococcal capsular polysaccharide, anti-Haemophilus influenzae, and anti-measles antibodies.

PK sampling should preferably be performed at Visit 4 (V4), provided that a stable dosing regimen has been maintained. Participants receiving IVIG on a 21-day schedule should collect seven samples at 30 minutes, 2 hours, 24 hours, 72 hours, 7 days, 14 days, and 21 days post-infusion. Participants receiving IVIG on a 28-day schedule should collect eight additional samples at 30 minutes, 2 hours, 24 hours, 72 hours, 14 days, 21 days, and 28 days post-infusion.

The PK profile should be evaluated only after at least four consecutive dosing intervals with no changes in posology, meaning both the dose and dosing interval remain unchanged, preferably at Visit 4 (V4). If any dose or interval adjustments occur between V0 and V4, PK profile sampling should be delayed until the next visit, after dosage stability is confirmed.

Participants will be contacted weekly between infusions to collect data on adverse events, concomitant medications, duration of infection treatment, and time lost from work or school due to infections during the period.

Additionally, subjects will have continued access to the investigator's team to report adverse events and to receive advice on next steps or additional medical evaluations, if necessary.

Medical evaluation, vital signs, and oximetry, adverse events, and concomitant medication will be assessed at all visits.

Safety laboratory tests (including direct Coombs and pregnancy tests) will be performed at every 4th or 5th visit.

Inclusion Criteria

1. Men or women; age between 02 and 60 years; written informed consent/assent.
2. Diagnosis of primary immunodeficiency disease (PID) with decreased antibody production due to common variable immunodeficiency (CVID) or X-linked agammaglobulinemia (XLA).
3. Treatment-naïve patients and those receiving intravenous immunoglobulin replacement therapy at 21- to 28-day intervals, with doses ranging from 300 to 800 mg/kg per infusion.
4. Negative pregnancy test in females of childbearing potential; willingness to use effective contraceptive methods throughout the study.
5. Subjects currently receiving any subcutaneous or intramuscular immunoglobulin may be enrolled by switching to IVIG therapy at the investigator's discretion, considering the potential benefit to the participant.

Exclusion Criteria Patients who meet any of the following criteria will be disqualified from participating.

1. Known intolerance or hypersensitivity to immunoglobulins or components of the study drug.

2. Any contraindications to the use of immunoglobulins.

3. Patients with a BMI < 18.5 or > 40 kg/m2.

4. Secondary immunodeficiency or clinical conditions that potentially cause secondary immunodeficiency, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, enteropathies, or nephropathies with protein loss and hypoalbuminemia.

5. Clinically significant changes in safety assessments, defined as:

   • Blood count

     • Hb < 10,5 g/dL
     • Leukocytes < 3,000 cells/mm3 or > 11,000 cells/mm3
     • Absolute neutrophil count < 1,000 cells/mm3

   • Coagulation:

     o PT and aPTT> 2,5 x ULN.

   • Biochemistry:

     • 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:

     • Clinically significant leukocyturia at the discretion of the investigator.

6. History of serious bacterial infections within three months before screening, presence of an active infection at the time of inclusion, and failure to fully resolve any non-serious infection at least two weeks before screening.

7. Any febrile illness in the 14 days before inclusion.

8. Any active or resolved cancer in the last 12 months before screening.

9. Receiving any blood products (except intravenous immunoglobulins) during the last 3 months before screening.

10. History of thrombotic events (including myocardial infarction, cerebral vascular accident [including stroke], pulmonary embolism, and deep vein thrombosis) within the last 6 months before enrollment or the presence of significant risk factors for thrombosis events.

11. Previous use of live attenuated virus vaccines within 3 months before enrollment.

12. Selective immunoglobulin A (IgA) deficiency or the presence of known antibodies against IgA.

13. Pregnancy, unreliable contraceptive methods, or lactation period (women only)

14. Known alcohol or drug abuse.

15. Patients with mental disorders that, in the investigator's opinion, may affect adherence to the protocol.

16. Other primary immunodeficiencies (PIDs) besides CVID or XLA.

17. Inability to comply with protocol activities.

18. Patients who are infected with HIV, HBV, HCV, or syphilis.

19. Any surgery scheduled to occur during the trial period.

20. Patients with cystic fibrosis

21. Patients with poorly controlled epilepsy, migraine, or hypertension (SBP ≥ 160 and/or DBP ≥ 100) managed with medication.

22. Subjects who have finished participation in a clinical trial with another experimental IVIG, less than one year before enrollment, may be included if they have a potential benefit as per CNS Res. 251/1997.

23. Any other medical condition that, in the investigator's opinion, may increase the risk of participation in this study.