Multicenter Randomized Controlled Trial Comparing Immunogenicity and Safety of Two Innovative Anti-pneumococcal Vaccine Strategies to Standard Vaccination Regimen in Patients With ANCA-associated Vasculitis Receiving Rituximab Therapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 96
- 试验地点
- 1
- 主要终点
- Immunogenicity
研究概览
简要总结
The study hypothesis is that a "reinforced" pneumococcal combined vaccine strategy in patients with ANCA-associated vasculitides treated with rituximab will induce a better immune response than the current standard regimen, with an acceptable safety profile.
This study therefore aims at evaluating the immunogenicity and safety of two "reinforced" innovative pneumococcal vaccine regimen [one double dose at day0 and one double dose at day7 or a quadruple dose of 13-valent anti-pneumococcal conjugate vaccine (PCV13) followed by one dose of 23-valent unconjugated vaccine (PPV23) at month 5], compared to the standard regimen (one dose of PCV13 followed by one dose of PPV23 at month 5), in patients with ANCA-associated vasculitides receiving rituximab therapy.
详细描述
Description of research methodology
Experimental plan This is a comparative, multicenter, prospective, randomized, open label, phase 2 trial in France, comparing two innovative "reinforced" anti-pneumococcal vaccine strategies to standard vaccination regimen in patients with ANCA-associated vasculitides receiving rituximab therapy.
Participants will be randomized 1:1:1 to three parallel arms to receive:
- Arm A (standard vaccination regimen): prime-boost strategy combining a single dose of 13-valent pneumococcal conjugate vaccine (Prevenar, PCV13) at Day 0 (lying within a window of ± 2 days of the first infusion of rituximab), followed by a single dose of 23-valent unconjugated vaccine (Pneumovax, PPV23) at month 5 (M5)
- Arm B (innovative vaccine strategy 1): prime-boost strategy combining 2 doses of PCV13 at Day 0 and 2 doses of PCV13 at Day 7, followed by a single dose of PPV23 at M5
- Arm C (innovative vaccine strategy 2): prime-boost strategy combining 4 doses of PCV13 at Day 0, followed by a single dose of PPV23 at M5
All participants will receive rituximab at 375 mg/m2/week for 4 consecutive weeks, at Days 0 ± 2 days, Day 7 ± 2 days, Day 14 ± 2 days and Day 21 ± 2 days, as induction therapy of vasculitis flare, followed by 500 mg-rituximab infusion every 6 months as maintenance therapy, i.e. at Month 6, Month 12 and Month 18 (Stone, NEJM, 2010, Jones, NEJM, 2010; Guillevin, NEJM, 2014), as recommended.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Outcomes Assessor)
盲法说明
The central laboratory performing the immunogenicity assessment (ELISA and OPA) will be blinded for the trial arm in order to limit measurement bias.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with a diagnosis of ANCA-associated vasculitis, either granulomatosis with polyangiitis (GPA, Wegener) or microscopic polyangiitis (MPA), according to ACR 1990 criteria and/or revised Chapel Hill Consensus Conference definitions and/or European Medical Agency algorithm
- •Participants (males and females) aged of 18 years or older
- •Participants with childbearing potential having reliable contraception for all the duration of the study, such as established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); barrier methods: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the vasectomized partner should be the sole partner for that subject); surgical sterilization (hysterectomy, bilateral oophorectomy, tubal ligation) or true abstinence (when this is in line with the preferred and usual lifestyle of the subject) prior to enrollment at D0
- •Participants with newly-diagnosed disease at the time of inclusion or presenting with a relapse of the disease. For relapsing patients, maintenance therapy at stable dose during the last 3 months will be admitted : prednisone dose ≤10 mg/day, azathioprine dose ≤3 mg/kg/day, methotrexate dose ≤25 mg/week, or mycophenolate mofetil dose ≤3 g/j
- •Participants with an active disease defined as a BVAS ≥ 3
- •Participants planned to receive rituximab as induction therapy using the recommended regimen (i.e. 375 mg/m2/week for 4 consecutive weeks)
- •Participants able to give written informed consent prior to participation in the study
- •Participants covered by social security regimen or equivalent
排除标准
- •Participants with eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) or other vasculitis
- •Participants with acute infections or chronic active infections at inclusion visit.
- •Documented positive serology result for HIV, HBV (Ag Hbs), HCV at inclusion.
- •Participants with disease associated with decreased immune response (splenectomy, hematopoietic stem cell transplantation, primary immune deficiency such as common variable immunodeficiency, cancer within the previous 5 years, drepanocytosis),
- •Participants treated with rituximab within the previous 12 months,
- •Participants who have received blood, blood products, and/or plasma derivatives including parenteral immunoglobulin preparations in the past 3 months before enrolment.
- •Participants treated with new other immunosuppressive or immunomodulatory agents within the previous 3 months (including cyclophosphamide, anti-TNF-alpha, intravenous immunoglobulins, abatacept),
- •Participants treated with prednisone dose >10 mg/day for a duration greater than 21 days before inclusion,
- •Participants with vaccination with a conjugate anti-pneumococcal vaccine at any time,
- •Participants with vaccination with PPV23 within the previous 3 years,
- •. Participants who have received any another vaccines within 4 weeks prior to enrolment or who are planning to receive any vaccine within the first 6 months of the study (except annual influenza vaccination and hepatitis B virus vaccination which are permitted before and after each vaccination visit of the study and then allowed at any time during the study follow up).
- •Pregnant women and lactation,
- •Participants with contraindication to use rituximab,
- •Participants with contraindication to intramuscular injections (hemophilia, anticoagulant therapy (excepted if subcutaneously), thrombocytopenia < 50 000/mm3).
- •Participants with hypersensitivity to previous vaccination
- •Participants with hypersensitivity to aluminium phosphate, phenol or protein CRM197 protein from Corynebacterium diphtheria.
- •Participants included in another investigational therapeutic study in the month prior D
- •Participation to an observational research is allowed.
- •Participants under legal guardianship or incapacitation
研究组 & 干预措施
Prime-boost strategy
a single dose of 13-valent pneumococcal conjugate vaccine (Prevenar, PCV13) at Day 0 (lying within a window of ± 2 days of the first infusion of rituximab), followed by a single dose of 23-valent unconjugated vaccine (Pneumovax, PPV23) at month 5 (M5)
干预措施: PCV13 (Biological)
Prime-boost strategy
a single dose of 13-valent pneumococcal conjugate vaccine (Prevenar, PCV13) at Day 0 (lying within a window of ± 2 days of the first infusion of rituximab), followed by a single dose of 23-valent unconjugated vaccine (Pneumovax, PPV23) at month 5 (M5)
干预措施: PPV23 (Biological)
Prime-boost strategy
a single dose of 13-valent pneumococcal conjugate vaccine (Prevenar, PCV13) at Day 0 (lying within a window of ± 2 days of the first infusion of rituximab), followed by a single dose of 23-valent unconjugated vaccine (Pneumovax, PPV23) at month 5 (M5)
干预措施: Rituximab (Drug)
Innovative vaccine strategy 1
2 doses of PCV13 at Day 0 and 2 doses of PCV13 at Day 7, followed by a single dose of PPV23 at M5
干预措施: PCV13 (Biological)
Innovative vaccine strategy 1
2 doses of PCV13 at Day 0 and 2 doses of PCV13 at Day 7, followed by a single dose of PPV23 at M5
干预措施: PPV23 (Biological)
Innovative vaccine strategy 1
2 doses of PCV13 at Day 0 and 2 doses of PCV13 at Day 7, followed by a single dose of PPV23 at M5
干预措施: Rituximab (Drug)
Innovative vaccine strategy 2
4 doses of PCV13 at Day 0, followed by a single dose of PPV23 at M5
干预措施: PCV13 (Biological)
Innovative vaccine strategy 2
4 doses of PCV13 at Day 0, followed by a single dose of PPV23 at M5
干预措施: PPV23 (Biological)
Innovative vaccine strategy 2
4 doses of PCV13 at Day 0, followed by a single dose of PPV23 at M5
干预措施: Rituximab (Drug)
结局指标
主要结局
Immunogenicity
时间窗: 6 months
Immune response at M6 against 12 pneumococcal serotypes, according to four ordered categories of response: positive response to 0-3, 4-6, 7-9, or 10-12 serotypes common to the PCV13 and PPV23 vaccines. This endpoint will be analyzed as the number and proportion of participants in each of the four response categories using a proportional odds model
次要结局
- Any adverse event during the trial related or possibly related to vaccine immunization(18 months)
- Local and/or systemic solicited reactions 7 days following each vaccination(18 months)