V-IMMUNE® for Primary Immunodeficiency: A Phase III Clinical Trial (VIP Study)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Safety outcome
研究概览
简要总结
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 total 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.
20 patients at total including adults and <16 years old, 6 children from 2 to 12 years old and 6 children from 12 to 16 years old.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
no masking
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 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.
- •Participants with through IgG measurements ≥700 mg/dL within the last 30 days before the first visit
排除标准
- •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
- •Selective 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 or 3x baseline value
- •Serum creatinine >2× the upper limit of normal or 2x baselline value
- •BUN >2.5× the upper limit of normal or 2.5x baseline value
- •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)
- •Observation:
- •If Research participant becomes pregnant during study participation - we will Discontinue any further administration of the IMP; The principal investigator must refer the research participant for follow-up through routine healthcare services; The research participant will continue to be monitored by the study; Obtain informed consent from the pregnant participant to request authorization to follow her pregnancy; If authorized by a specific informed consent form, even after the participant's involvement in the study has ended, the investigator must contact the pregnant participant quarterly to monitor the pregnancy. The results of this follow-up must be entered into the CRF. The frequency will be maintained as long as no abnormalities are identified in the participant, the pregnancy, or the fetus.
- •Female partner of a male research participant becomes pregnant during the study = No action is required regarding the research participant's participation; Obtain informed consent from the research participant's partner to request authorization to monitor her pregnancy. If authorized by a specific informed consent form, the investigator must contact the pregnant woman quarterly to monitor the pregnancy. The results of this follow-up must be entered into the CRF. The frequency will be maintained as long as no abnormalities are identified in the pregnant woman, the pregnancy, or the fetus.
- •Data Confidentiality:
- •The confidentiality of data from all patients will be ensured and preserved. Patient identification will be performed exclusively through the study-assigned identification number, the patient's initials, and date of birth. An exception to this procedure applies to participants included in the pharmacokinetic analyses, who, after providing consent themselves or through their legal representative, will also have their personal identifying data (full name, CPF [Brazilian individual taxpayer registry number], date of birth, and sex), as well as information regarding their participation (date of study enrollment), collected and transferred to the ICF laboratory for registration in the SINEB system (Sistema de Informações de Estudos de Equivalência Farmacêutica e Bioequivalência), an ANVISA database used for the registration of participants in studies of this nature.
- •Data obtained from medical records and other documents will be maintained in a confidential manner by the research centers and stored in locations with restricted access limited to the study team. Sensitive data, such as patient contact information collected for scheduling and follow-up purposes, will be accessed exclusively by personnel involved in the conduct of the study. The principal investigator shall allow direct access to participants' records and source documents for the purposes of monitoring, auditing, or inspection by the Sponsor and Regulatory Authorities, if required.
- •With regard to participants included in the pharmacokinetic analyses, the collection of personal identifying data (full name, CPF [Brazilian individual taxpayer registry number], date of birth, and sex) and participation-related information (date of study enrollment) is planned for transfer to the ICF laboratory for registration in the SINEB database. This procedure aims to mitigate risks to research participants by ensuring that they are not concurrently enrolled in another study within an interval shorter than six (6) months.
研究组 & 干预措施
Intervention arm
Human normal immunoglobulin I.P. 5% (5 g/100 mL) V-IMMUNE® will be administered at a dose of 600 mg/kg every 3 weeks (±3 days) via intravenous (IV) infusion according to the rate below, over a duration of 3 to 6 hours (4):
0.01 mL/kg/min from 0 to 30 minutes, followed by the following infusion rates:
0.02 mL/kg/min from 31 to 45 minutes
0.04 mL/kg/min from 46 to 60 minutes
0.06 mL/kg/min from 61 minutes until the end of the infusion
The dose increases gradually unless adverse events (AEs) occur. The infusion rate is only increased if the patient tolerates it well, with no AEs.
If an AE occurs, the infusion must be interrupted for 20 to 30 minutes. Pre-medication: 30 to 60 min before Ig
Rapid administration of 500 mL of 0.9% NaCl IV
Diphenhydramine* 50 mg IV (adult). Pediatrics: 1.25 mg/kg IV
Hydrocortisone** 200 mg IV (adult). Pediatrics: 3 mg/kg IV
After infusion: 0.9% NaCl at 1 mL/kg/hour for one hour
In case of thromboembolic risk: use the lowest feasible infusion rate
干预措施: Intravenous immunoglobulin (IVIG) (Biological)
结局指标
主要结局
Safety outcome
时间窗: 72 hours
Proportion of infusions with one or more temporally associated adverse events (AEs)
Efficacy primary outcome
时间窗: 12 months
The primary efficacy endpoint is the rate of serious bacterial infections per person-year. These serious bacterial infection are: bacteremia/sepsis, bacterial meningitis, osteomielitis/septic arthritis, bacterial pneumonia, visceral abscess
次要结局
- Infection resolution time(12 months)
- Nadir of pre-infusion total IgG level(3 weeks)
- Hospitalizations due to infections(12 months)
- Secondary safety outcome(12 months)
- Severe and non-severe bacterial infections(12 months)
- Number of patients with 0, 1, 2, etc., severe infections(12 months)
- Number of adverse events by body systems(12 months)
- Time to first infection(12 months)
- Episodes of fever(12 months)
- Nadir of pre-infusion total IgG level in children aged 2 to <16 years(3 weeks after the fifth infusion)
- Number of any severe or non-severe infection(12 months)
- Use of antibiotics(12 months)
- Quality of life: Short Form Health Survey (36)(6 and 12 months)
- Number of days absent from school or work(12 months)
- Minimum total IgG level (500 mg/dL) not reached(12 months)
- Trough total IgG measurement(12 months)
- Number of adverse events by cardiovascular, gastrointestinal, neurological, renal, hepatic, motor, and respiratory system assessed by CTCAE 4.0(12 months)
- Proportion of participants who could not reach minimum target level of Total Immunoglobulin ≥ 500 mg/dL(5 estimated half-lives)
- Trough total IgG level per infection(at each occurrence of an infection.)