A Phase III Randomized Controlled Multi-centre Trial to Evaluate the Efficacy of the R21/Matrix-M Vaccine in African Children Against Clinical Malaria
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 4,800
- 试验地点
- 1
- 主要终点
- Efficacy: To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-36 month old children living in a malaria endemic area, 12 months after completion of the primary course.
研究概览
简要总结
A Phase III randomized controlled multi-centre trial to evaluate the efficacy of the R21/Matrix-M vaccine in African children against clinical malaria
详细描述
This will be a double-blind, individually randomised trial. In the first phase of the trial, participants were randomised 2:1 to receive R21/Matrix-M malaria vaccine or a control rabies vaccine (Abhayrab). The study groups are as follows:
Standard vaccination regime, 5-36 months olds R21/Matrix-M x 3, n = 1600 Control (rabies) vaccine x 3, n = 800
Seasonal vaccination regime, 5-36 month olds R21/Matrix-M x 3, n = 1600 Control (rabies) vaccine x 3, n = 800
In each group, a booster (4th) dose of the same vaccine will be administered 12 months after the third dose. At certain trial sites, participants in the malaria vaccine group may be further randomised 1:1 to receive a single-vial: two-vial formulation of R21/Matrix-M.
The trial has been extended for two further years to assess safety and efficacy over a longer period of time. During this time, it will also assess the safety, immunogenicity and efficacy of second and third booster doses.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double blind
入排标准
- 年龄范围
- 5 Months 至 36 Months（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •All participants must satisfy the following criteria at study entry:
- •The child is 5-36 months of age at the time of first vaccination.
- •Signed informed consent/thumb-printed and witnessed informed consent obtained from the parent(s)/guardian(s) of the child to join the trial.
- •The investigator believes that the parents/guardians can and will comply with the requirements of the protocol if the child is enrolled in the study.
- •The child is a permanent resident of the study area and likely to remain a resident for the duration of the trial.
排除标准
- •The following criteria should be checked at the time of study entry. If any apply, the participant must not be included:
- •The child has previously received a malaria vaccine.
- •The child is enrolled in another malaria intervention trial.
- •The child has a history of allergic disease or reactions likely to be exacerbated by any component of the malaria or control vaccine.
- •The child has a history of allergic reactions, significant IgE-mediated events or anaphylaxis to previous immunisations.
- •The child has major congenital defects.
- •The child has anaemia associated with clinical signs of symptoms of decompensation, or a haemoglobin of ≤ 5.0 g/dL.
- •The child has had a blood transfusion within one month of enrolment.
- •The child has been administered immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate.
- •The child has malnutrition requiring hospital admission.
- •The child has an acute or chronic, clinically significant pulmonary, cardiovascular, gastrointestinal, endocrine, neurological, skin, hepatic or renal functional abnormality, as determined by medical history, physical examination or laboratory tests.
- •Children currently meeting the WHO criteria for HIV disease of stage 3 or 4 severity. A previous history of stage 3 or 4 disease is not an exclusion. Note: There will be no routine testing for HIV. Positive diagnoses will be recorded at screening if known.
- •The child has received an investigational drug or vaccine other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period.
- •The child is currently participating in another clinical trial if likely to affect data interpretation of this trial
- •The child has any significant disease, disorder or situation which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.
- •Additional exclusion criteria for second phase of the trial (addition of second and third booster doses)
- •- Hypersensitivity to neomycin (Hepatitis A vaccine may contain traces of this).
研究组 & 干预措施
Standard Regime - Group 1-1
R21/Matrix-M at primary series and first booster, control vaccine at second and third booster, n = 400, 5-36 months olds
干预措施: R21/Matrix-M (Biological)
Standard Regime - Group 1-1
R21/Matrix-M at primary series and first booster, control vaccine at second and third booster, n = 400, 5-36 months olds
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
Standard Regime - Group 1-2
R21/Matrix-M at primary series, first booster and second booster, control vaccine at third booster, n = 400, 5-36 months olds
干预措施: R21/Matrix-M (Biological)
Standard Regime - Group 1-2
R21/Matrix-M at primary series, first booster and second booster, control vaccine at third booster, n = 400, 5-36 months olds
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
Standard Regime - Group 1-3
R21/Matrix-M at primary series and first booster, control vaccine at second booster and R21/Matrix-M at third booster, n = 400, 5-36 months olds
干预措施: R21/Matrix-M (Biological)
Standard Regime - Group 1-3
R21/Matrix-M at primary series and first booster, control vaccine at second booster and R21/Matrix-M at third booster, n = 400, 5-36 months olds
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
Standard Regime - Group 1-4
R21/Matrix-M at primary series, first booster, second booster and third booster, n = 400, 5-36 months olds
干预措施: R21/Matrix-M (Biological)
Standard Regime - Group 2
Control vaccine at primary series, first booster, second booster and third booster, n=800, 5-36 month olds
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
Seasonal Regime - Group 5
Group 3-1 for the initial part of the trial and first extension - R21/Matrix-M at primary series and first booster, control vaccine at second and third booster, n = 400, 5-36 months olds.
For the school age booster extension, group 3-1 has been randomised into two groups: group 5 and 6. Group 5 will receive another dose of R21/Matrix-M.
干预措施: R21/Matrix-M (Biological)
Seasonal Regime - Group 5
Group 3-1 for the initial part of the trial and first extension - R21/Matrix-M at primary series and first booster, control vaccine at second and third booster, n = 400, 5-36 months olds.
For the school age booster extension, group 3-1 has been randomised into two groups: group 5 and 6. Group 5 will receive another dose of R21/Matrix-M.
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
Seasonal Regime - Group 3-2
R21/Matrix-M at primary series, first booster and second booster, control vaccine at third booster, n = 400, 5-36 months olds.
For the school age booster extension, this group will receive no further vaccination and will be followed up for a further two years.
干预措施: R21/Matrix-M (Biological)
Seasonal Regime - Group 3-2
R21/Matrix-M at primary series, first booster and second booster, control vaccine at third booster, n = 400, 5-36 months olds.
For the school age booster extension, this group will receive no further vaccination and will be followed up for a further two years.
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
Seasonal Regime - Group 3-3
R21/Matrix-M at primary series and first booster, control vaccine at second booster and R21/Matrix-M at third booster, n = 400, 5-36 months olds.
For the school age booster extension, this group will receive no further vaccination and will be followed up for a further two years.
干预措施: R21/Matrix-M (Biological)
Seasonal Regime - Group 3-3
R21/Matrix-M at primary series and first booster, control vaccine at second booster and R21/Matrix-M at third booster, n = 400, 5-36 months olds.
For the school age booster extension, this group will receive no further vaccination and will be followed up for a further two years.
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
Seasonal Regime - Group 3-4
R21/Matrix-M at primary series, first booster, second booster and third booster, n = 400, 5-36 months olds.
For the school age booster extension, this group will receive no further vaccination and will be followed up for a further two years.
干预措施: R21/Matrix-M (Biological)
Seasonal Regime - Group 4
Control vaccine at primary series, first booster, second booster and third booster, n=800, 5-36 month olds.
For the school age booster extension, this group will receive one further booster of the control vaccine.
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
Seasonal Regime - Group 6
Group 3-1 for the initial part of the trial and first extension - R21/Matrix-M at primary series and first booster, control vaccine at second and third booster, n = 400, 5-36 months olds.
For the school age booster extension, group 3-1 has been randomised into two groups: group 5 and 6. Group 6 will receive a control vaccine.
干预措施: R21/Matrix-M (Biological)
Seasonal Regime - Group 6
Group 3-1 for the initial part of the trial and first extension - R21/Matrix-M at primary series and first booster, control vaccine at second and third booster, n = 400, 5-36 months olds.
For the school age booster extension, group 3-1 has been randomised into two groups: group 5 and 6. Group 6 will receive a control vaccine.
干预措施: Rabies vaccine, Hepatitis A vaccine or Meningococcal vaccine (Biological)
结局指标
主要结局
Efficacy: To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-36 month old children living in a malaria endemic area, 12 months after completion of the primary course.
时间窗: 2 years
The primary efficacy outcome is clinical malaria, according to the primary case definition: the presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours, and P. falciparum asexual parasitaemia \>5000 parasites/μL.This will assessed separately for seasonal and standard vaccination regimes.
Safety: To assess the safety and reactogenicity of R21/Matrix-M, in both vaccination regimes, of children living in a malaria endemic area, in the month following each vaccination, and 12 months after completion of the primary course.
时间窗: 2 years
* Occurrence of solicited local reactogenicity signs and symptoms for 7 days following the vaccination. * Occurrence of solicited systemic reactogenicity signs and symptoms for 7 days following the vaccination. * Occurrence of unsolicited adverse events for 28 days following the vaccination. * Change from baseline for safety laboratory measures thought to be clinically significant. * Occurrence of serious adverse events for the whole study duration.
School age booster extension: To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum in school- age children in Burkina Faso and Mali
时间窗: 12 months and 24 months after school age booster
* To assess the protective efficacy of an additional late booster of R21/Matrix-M at 24 months against clinical malaria, in school-age children who have previously received four doses of R21/Matrix-M. * To assess the protective efficacy of R21/Matrix-M at 24 months against clinical malaria, in school- age children, who have previously received four doses of R21/Matrix-M. * To assess the protective efficacy of R21/Matrix-M at 12 months against clinical malaria, in school- age children, who have previously received a fifth dose one year after the fourth dose, a delayed fifth dose or six doses of R21/Matrix-M. * To assess the protective efficacy of R21/Matrix-M at 12 months against clinical malaria, in school- age children who have previously received a fifth dose one year after the fourth dose, a delayed fifth dose or six doses of R21/Matrix-M compared to those who received 4 doses.
School age booster extension: to assess the safety and reactogenicity of an additional late booster of R21/Matrix-M, in school age children living in Burkina Faso and Mali, one month after vaccination
时间窗: One month after the school age booster
This will be measured through the occurrence of local and systemic reactogenicity signs and symptoms for 7 days following the school age booster, and the occurrence of unsolicited adverse events for 28 days following this booster.
次要结局
- Protective efficacy of R21/Matrix-M against clinical malaria caused by P.falciparum, in 5-36 month old children living in a malaria endemic area, following the primary vaccination series across both vaccination regimes and following booster vaccinations.(2 years)
- Efficacy of R21/Matrix-M against asymptomatic P.falciparum malaria infection in either vaccination regime, following the primary vaccination series and following each booster vaccination.(2 years)
- Efficacy of R21/Matrix-M against severe malaria disease in either vaccination regime, following the primary vaccination series and following each booster vaccination.(2 years)
- Efficacy of R21/Matrix-M against clinical malaria according to different transmission settings (seasonal and standard vaccination regimes).(2 years)
- Efficacy of R21/Matrix-M against incident severe anaemia and the need for blood transfusion in both vaccination regimes following the primary vaccination series and each booster vaccination.(2 years)
- Efficacy of R21/Matrix-M against malaria hospitalisation following the primary vaccination series and each booster vaccination.(2 years)
- Safety, reactogenicity, humoral immunogenicity and efficacy of R21/Matrix-M as a single-vial formulation, compared with the two-vial formulation.(2 years)
- Safety and reactogenicity (including Serious adverse events (SAEs) and any deaths) following each booster vaccination and for the duration of the study.(2 years)
- Humoral immunogenicity by anti-CSP antibody concentrations measured 12 months after completion of the primary series of 3 vaccinations and 12 months after each booster vaccination.(2 years)
- School age booster extension: Efficacy(6, 12, 18 and 24 months after receiving a school age booster)
- School age booster extension: Safety and reactogenicity(Two years after school age booster)
- School age booster: Immunogenicity(28 days post school age booster, 1 year post school age booster and 2 years post school age booster)
- School age booster extension: Impact(2 years after school age booster)