Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG

Primary Immunodeficiency Disease Clinical Trial

— Imunoforte  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06089122
• Other study ID #: IMUNOFORTE
• Secondary ID: U1111-1298-7059
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 2024
• Est. completion date: June 8, 2025

Study information

• Verified date: October 2023
• Source: Azidus Brasil
• Contact: Luciana Ferrara
• Phone: +55 19 981428814
• Email: luciana.ferrara[@]azidusbrasil.com.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: June 8, 2025
• Est. primary completion date: January 8, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Written informed consent/assent.

2. Male or female.

3. Ages = 60 years old and = 06 years old.

4. 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.

5. 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;

6. Absence of episodes of serious bacterial infections with previous use of an IV immunoglobulin for at least 3 months before screening;

7. Negative pregnancy test (in female patients with childbearing potential); readiness to use reliable methods of contraception throughout the study period;

8. 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;

9. 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:

1. Known intolerance or hypersensitivity to immunoglobulins or components of the test article;

2. Any contraindications to the use of immunoglobulins;

3. Secondary immunodeficiency or conditions potentially causing secondary immunodeficiency such as chronic lymphoid leukemia, lymphoma, multiple myeloma, protein-losing enteropathies or nephropathies, and hypoalbuminemia;

4. 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.

Related Conditions & MeSH terms

• Immunologic Deficiency Syndromes
• Primary Immunodeficiency Disease
• Primary Immunodeficiency Diseases

Intervention

Biological:
• IVIG
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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Azidus Brasil	Sichuan Yuanda Shuyang Pharmaceutical Co., Ltd.

References & Publications (22)

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Blasczyk R, Westhoff U, Grosse-Wilde H. Soluble CD4, CD8, and HLA molecules in commercial immunoglobulin preparations. Lancet. 1993 Mar 27;341(8848):789-90. doi: 10.1016/0140-6736(93)90563-v. — View Citation

Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, Espinosa-Rosales FJ, Hammarstrom L, Nonoyama S, Quinti I, Routes JM, Tang ML, Warnatz K. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016 Jan-Feb;4(1):38-59. doi: 10.1016/j.jaip.2015.07.025. Epub 2015 Nov 7. — View Citation

BRUTON OC. Agammaglobulinemia. Pediatrics. 1952 Jun;9(6):722-8. No abstract available. — View Citation

Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2002 Jun;109(6):1001-4. doi: 10.1067/mai.2002.124999. — View Citation

Cordero E, Goycochea-Valdivia W, Mendez-Echevarria A, Allende LM, Alsina L, Bravo Garcia-Morato M, Gil-Herrera J, Gudiol C, Len-Abad O, Lopez-Medrano F, Moreno-Perez D, Munoz P, Olbrich P, Sanchez-Ramon S, Soler-Palacin P, Aguilera Cros C, Arostegui JI, Badell Serra I, Carbone J, Fortun J, Gonzalez-Granado LI, Lopez-Granados E, Lucena JM, Parody R, Ramakers J, Regueiro JR, Riviere JG, Roca-Oporto C, Rodriguez Pena R, Santos-Perez JL, Rodriguez-Gallego C, Neth O. Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies. J Allergy Clin Immunol Pract. 2020 Nov-Dec;8(10):3342-3347. doi: 10.1016/j.jaip.2020.05.008. — View Citation

Hagan JB, Fasano MB, Spector S, Wasserman RL, Melamed I, Rojavin MA, Zenker O, Orange JS. Efficacy and safety of a new 20% immunoglobulin preparation for subcutaneous administration, IgPro20, in patients with primary immunodeficiency. J Clin Immunol. 2010 Sep;30(5):734-45. doi: 10.1007/s10875-010-9423-4. Epub 2010 May 8. — View Citation

Hartung HP, Mouthon L, Ahmed R, Jordan S, Laupland KB, Jolles S. Clinical applications of intravenous immunoglobulins (IVIg)--beyond immunodeficiencies and neurology. Clin Exp Immunol. 2009 Dec;158 Suppl 1(Suppl 1):23-33. doi: 10.1111/j.1365-2249.2009.04024.x. — View Citation

Herriot R, Sewell WA. Antibody deficiency. J Clin Pathol. 2008 Sep;61(9):994-1000. doi: 10.1136/jcp.2007.051177. — View Citation

Hoffmann F, Grimbacher B, Thiel J, Peter HH, Belohradsky BH; Vivaglobin Study Group. Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency. Eur J Med Res. 2010 Jun 28;15(6):238-45. doi: 10.1186/2047-783x-15-6-238. — View Citation

IDF Guide for Nurses - Immunoglobulin Therapy for Primary Immunodeficiency Diseases. 4th, pp. 59.

Milito C, Pulvirenti F, Pesce AM, Digiulio MA, Pandolfi F, Visentini M, Quinti I. Adequate patient's outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies. J Clin Immunol. 2014 Oct;34(7):813-9. doi: 10.1007/s10875-014-0081-9. Epub 2014 Jul 22. — View Citation

Mouthon L, Kaveri SV, Spalter SH, Lacroix-Desmazes S, Lefranc C, Desai R, Kazatchkine MD. Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clin Exp Immunol. 1996 May;104 Suppl 1:3-9. — View Citation

Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, Buckley R, Chinen J, El-Gamal Y, Mazer BD, Nelson RP Jr, Patel DD, Secord E, Sorensen RU, Wasserman RL, Cunningham-Rundles C; Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006 Apr;117(4 Suppl):S525-53. doi: 10.1016/j.jaci.2006.01.015. Erratum In: J Allergy Clin Immunol. 2006 Jun;117(6):1483. Dosage error in article text. — View Citation

Pourpak Z, Aghamohammadi A, Sedighipour L, Farhoudi A, Movahedi M, Gharagozlou M, Chavoshzadeh Z, Jadid L, Rezaei N, Moin M. Effect of regular intravenous immunoglobulin therapy on prevention of pneumonia in patients with common variable immunodeficiency. J Microbiol Immunol Infect. 2006 Apr;39(2):114-20. — View Citation

Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol. 1999 Oct;118 Suppl 1(Suppl 1):1-28. doi: 10.1046/j.1365-2249.1999.00109.x. No abstract available. — View Citation

Quinti I, Soresina A, Guerra A, Rondelli R, Spadaro G, Agostini C, Milito C, Trombetta AC, Visentini M, Martini H, Plebani A, Fiorilli M; IPINet Investigators. Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: results from a multicenter prospective cohort study. J Clin Immunol. 2011 Jun;31(3):315-22. doi: 10.1007/s10875-011-9511-0. Epub 2011 Mar 2. — View Citation

Radosevich M, Burnouf T. Intravenous immunoglobulin G: trends in production methods, quality control and quality assurance. Vox Sang. 2010 Jan;98(1):12-28. doi: 10.1111/j.1423-0410.2009.01226.x. Epub 2009 Jul 29. — View Citation

Salehzadeh M, Aghamohammadi A, Rezaei N. Evaluation of immunoglobulin levels and infection rate in patients with common variable immunodeficiency after immunoglobulin replacement therapy. J Microbiol Immunol Infect. 2010 Feb;43(1):11-7. doi: 10.1016/S1684-1182(10)60002-3. Epub 2010 Mar 29. — View Citation

Suri D, Rawat A, Singh S. X-linked Agammaglobulinemia. Indian J Pediatr. 2016 Apr;83(4):331-7. doi: 10.1007/s12098-015-2024-8. Epub 2016 Feb 24. — View Citation

WHO. WHO RECOMMENDATIONS FOR THE PRODUCTION, CONTROL AND REGULATION OF HUMAN PLASMA FOR FRACTIONATION. pp. 69.

Yazdani R, Habibi S, Sharifi L, Azizi G, Abolhassani H, Olbrich P, Aghamohammadi A. Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management. J Investig Allergol Clin Immunol. 2020;30(1):14-34. doi: 10.18176/jiaci.0388. Epub 2019 Feb 11. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Secondary Pharmacokinetic (PK) Objectives	To assess the total IgG serum concentration before each infusion (IgG trough levels), between Visit 4 and Final Visit (through study completion).	9 months
Other	Secondary Pharmacokinetic (PK) Objectives	To assess total serum IgG profile (concentration vs time) at specific times between the 5th and 6th infusion	28 days
Other	IgG half-life	Determine IgG half-life from concentration vs time curve	28 days
Other	Area under the IgG curve	Determine IgG AUC from concentration vs time curve	28 days
Other	IgG distribution volume	Determine IgG Vd from concentration vs time curve	28 days
Other	IgG elimination constant	Determine IgG Kel from concentration vs time curve	28 days
Other	Incidence, severity, and causality of adverse events	Assessment of infusion-related adverse events;	1, 24, and 72 hours after each infusion (through study completion, an average of 1 year);
Other	Secondary Safety Objective	Assessment of treatment emergent adverse events (TEAEs).	Incidence, severity, and causality of all treatment-emergent adverse events, except those infusion-related (through study completion, an average of 1 year).
Primary	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	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	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	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	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).