Efficacy and Safety and Pharmacokinetics of Boya IVIG

Primary Immunodeficiency Disease Clinical Trial

— Boya  

Official title:

Efficacy, Safety and Pharmacokinetics of Boya Intravenous Immunoglobulin (IVIG) in Participants With Primary Immunodeficiency

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06150833
• Other study ID #: BoyaIVIG
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 1, 2024
• Est. completion date: September 30, 2025

Study information

• Verified date: November 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 Boya's IVIG preparation in participants with PID aged less than 60 years and more than 6 years.

Description:

This is a phase 3, open-label, prospective, single-group, multicenter study to evaluate the efficacy of IVIG in keeping the average number of serious bacterial infections to less than one per year. The safety and pharmacokinetics (PK) of the investigational product will also be assessed. Fifty male or female participants aged up to 60 years will be selected, with at least 20 participants aged between 06 and 17 years. During the study, at least 20 adult participants will be invited to make up the subgroups evaluating the pharmacokinetic parameters.

The main benefit of IVIG is to help the immune system respond to a wide range of infections, which are often correlated with high morbidity and mortality rates in individuals with PID, particularly in cases of CVID and XLA. In addition, a reduction in the use of medication and hospitalizations is expected, promoting an improvement in the quality of life of these patients.

IVIG therapy is generally safe, although unwanted effects are reported in a proportion ranging from 1% to 81% of patients or infusions, with an average incidence of 30% to 40% among patients and 5% to 15% among infusions. These effects can manifest themselves in varying degrees of intensity, ranging from mild to severe. They can occur immediately, during or shortly after the infusion, as well as late, appearing hours or even days after the procedure. Most adverse events are mild and immediate, occurring in the first few infusions, related to the infusion rate and quickly reversible.

Headache, fever, general malaise, flu-like symptoms, nausea, chills, fatigue, myalgia, low back pain, tachycardia, changes in blood pressure and erythroderma are the most common events. Serious reactions occur in less than 1% of applications and usually with the use of higher doses, indicated in autoimmune and inflammatory diseases.

Special care is needed in patients with comorbidities such as heart disease, nephropathy, liver disease, coagulation disorders (thrombophilia) and diabetes mellitus. In these patients, certain characteristics of IVIG should be assessed, such as the presence of sugars, osmolality, sodium, among others.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: September 30, 2025
• Est. primary completion date: April 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Signature of written informed consent.

2. Men or women.

3. Age = 60 years.

4. Diagnosis of PID disease (PID) with a reduction in antibody production due to:

1. Common variable immunodeficiency (CVID) as defined ESID/PAGID, OR

2. X-linked agammaglobulinemia (XLA) as defined by ESID/PAGID.

5. Receiving intravenous immunoglobulin replacement therapy at 21- or 28-day intervals at 300 to 600 mg/kg/month for a minimum of 2 months prior to study entry.

6. Absence of episodes of serious bacterial infections with prior use of IV immunoglobulin for at least 3 months prior to screening.

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

8. Patients who have participated in a clinical study with another investigational IVIG may be included if they have a potential benefit in accordance with CNS Res. 251/1997.

9. Participants undergoing treatment with any subcutaneous or intramuscular immunoglobulin may be included by switching to IVIG therapy at the discretion of the investigator, considering the possible benefit to the participant.

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

• Hb < 10.5 g/dL

• Leukocytes < 3,000 / mm3 or >10,000 cells / mm3

• Absolute neutrophil count < 1,000 cells/mm3;

• Coagulation

• TP 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.

• 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:
• Boya IVIG
The initial dose and other dose changes will be determined by the investigator on a case-by-case basis aiming to prevent infection and minimum serum IgG levels of 5 g/L. The total number of doses administered will depend on the treatment regimen and run-in period: Between 16 and 20 intravenous injections for participants receiving infusions every 28 days, or; Between 21 and 25 intravenous injections for participants receiving infusions every 21 days

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Azidus Brasil	Boya Bio Pharmaceutical Group Co Ltd

References & Publications (35)

Bierry G, Boileau J, Barnig C, Gasser B, Korganow AS, Buy X, Jeung MY, Roy C, Gangi A. Thoracic manifestations of primary humoral immunodeficiency: a comprehensive review. Radiographics. 2009 Nov;29(7):1909-20. doi: 10.1148/rg.297095717. — View Citation

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

Brasil (2008) Diretrizes Operacionais para o estabelecimento e o funcionamento de comitês de monitoramento de dados e segurança. Brasília, pp. 44.

Brasil (2018). Lei Geral de Proteção de Dados. 14ago2018. Disponível em: https://www.planalto.gov.br/ccivil_03/_ato2015-2018/2018/lei/L13709compilado.htm. Acessado em 09nov23.

Brasil, Resolução nº 251, de 07 de agosto de 1977. Disponível em; https://www.inca.gov.br/sites/ufu.sti.inca.local/files//media/document//resolucao-cns-251-97.pdf. Acesso em 25 de out de 2023

Brasil. Manual de orientação: pendências frequentes em protocolo de pesquisas. Disponível em: https://conselho.saude.gov.br/Web_comissoes/conep/aquivos/documentos/MANUAL_ORIENTACAO_PENDENCIAS_FREQUENTES_PROTOCOLOS_PESQUISA_CLINICA_V1.pdf. Acesso em: 26out2023

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

Conselho das Organizações Internacionais de Ciências Médicas (CIOMS) em colaboração com a Organização Mundial da Saúde (2016). Diretrizes éticas internacionais para pesquisas relacionadas a saúde envolvendo seres humanos. Disponível em: https://cioms.ch/wp-content/uploads/2018/11/CIOMS-final-Diretrizes-Eticas-Internacionais-Out18.pdf. Acesso em: 31out2023

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. Enferm Infecc Microbiol Clin (Engl Ed). 2020 Nov;38(9):438-443. doi: 10.1016/j.eimc.2020.07.001. English, Spanish. — View Citation

EMA/CHMP/BPWP/94033/2007 rev. 4. Guideline on the clinical investigation of human normal immunoglobulin for intravenous administration (IVIg), Sep,2020.

Food and Drug Administration (2006). Guidance for Clinical Trial Sponsors on the Establishment and Operation of Clinical Trial Data Monitoring Committees. Rockville, MD, pp. 38.

Goudouris ES, Rego Silva AM, Ouricuri AL, Grumach AS, Condino-Neto A, Costa-Carvalho BT, Prando CC, Kokron CM, Vasconcelos DM, Tavares FS, Silva Segundo GR, Barreto IC, Dorna MB, Barros MA, Forte WCN. II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies. Einstein (Sao Paulo). 2017;15(1):1-16. doi: 10.1590/S1679-45082017AE3844. Erratum In: Einstein (Sao Paulo). 2017 Jul-Sep;15(3):387. — View Citation

Guidance for Industry: Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency. Rockville, MD, pp. 17, Jun,2008.

Harmonisation for better health (1998). Statitical Principles for Clinical Trials E9. Disponível em: Disponível em: https://database.ich.org/sites/default/files/E9_Guideline.pdf Acesso em: 01nov2023

Harmonisation for better health (1998). The Guideline Statistical Principles for Clinical Trials E9 (R1). Disponível em: https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf Acesso em: 01nov2023

Harmonisation for better health (2016). Guideline for Good Clinical Practice. Disponível em: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf Acesso em: 01nov2023

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

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

Mongkonsritragoon W, Srivastava R, Seth D, Navalpakam A, Poowuttikul P. Non-infectious Pulmonary Complications in Children with Primary Immunodeficiency. Clin Med Insights Pediatr. 2023 Sep 8;17:11795565231196431. doi: 10.1177/11795565231196431. eCollection 2023. — 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

Organização Pan-Americana da Saúde (2005). Boas Práticas Clínicas: Documentos das Américas. Disponível em: https://www.gov.br/anvisa/ptbr/centraisdeconteudo/publicacoes/medicamentos/pesquisa-clinica/manuais-e-guias/documento-das-americas-boas-praticas-clinicas.pdf/view. Acesso em: 01out2023

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

World Health Organization (2005) Recommendations for the production, control and regulation of human plasma for fractionation, Annex 4, TRS nº 941, pp. 69.

World Health Organization (2009). Conceptual Framework of the International Classification for Patient safety. World Health Organization, Patient Safety. Quem Press.

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 35 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	Assessment of the rate of non-serious infections within one year	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	Length of infections	Assessment of the duration of treatment for 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	Missing time from school/work	Assessment of time lost at 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	Hospitalization episodes	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)