| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy volunteers (Primary and booster immunization against Plasmodium falciparum malaria) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Parasitic Diseases [C03] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-To evaluate the protective efficacy of RTS,S/AS01E against clinical malaria disease caused by Plasmodium falciparum in African children whose age at first dose will be from 6-12 weeks and will receive vaccine in co-administration with DTPwHepB/Hib antigens (Tritanrix HepB/Hib) and OPV. Duration of follow up will be for a minimum of 12 months and a maximum of 18 months after completion of the primary course (Primary Analysis).
-To evaluate the protective efficacy of RTS,S/AS01E against clinical malaria disease caused by Plasmodium falciparum in African children whose age at first dose will be from 5-17 months. Duration of follow up will be for a minimum of 12 months and a maximum of 18 months after completion of the primary course (Primary Analysis). |
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| E.2.2 | Secondary objectives of the trial |
To evaluate:
-the efficacy of RTS,S/AS01E on a primary schedule with and without a boost against severe malaria disease, incident severe anaemia, clinical malaria disease under different transmission settings, secondary case definitions of clinical malaria and other parameters*
-the duration of efficacy of RTS,S/AS01E with and without boost against clinical malaria
-the anti-CS, anti-HBs and anti-polio 1, 2 and 3 antibody responses
-the safety of a primary schedule and of a booster dose of RTS,S/AS01E
-the efficacy of RTS,S/AS01E by gender
-the association between CS-antibody response and protection against malaria.
-the safety and immunogenicity in special subgroups
-the number of cases averted of clinical malaria, severe malaria, and other parameters*
-the effect of RTS,S/AS01E on growth
*Other parameters: malaria hospitalization, prevalence of para-sitemia, prevalence of moderate and severe anaemia, all-cause mortality, fatal malaria, other serious illnesses
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All subjects must satisfy the following criteria at study entry:
-A male or female child of 5-17 months (inclusive) of age at time of first vaccination, or between 6-12 weeks (inclusive) of age at time of first vaccination and NOT have already received a dose of vaccine against diphtheria, tetanus or pertussis or Hemophilus influenzae type B and must be > 28 days of age at screening.
-Signed informed consent or thumb-printed and witnessed informed consent obtained from the parent(s)/guardian(s) of the child.
-Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol (e.g. return for follow-up visits) should be enrolled in the study.
All subjects must satisfy the following criteria at the start of the extension phase:
-Subjects who were enrolled and who received at least one vaccine dose in the primary trial phase.
-Subjects who were present for Visit 35 on or before 30 Sep-tember 2013.
-Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol (e.g. return for follow-up visits) should be enrolled in the study. |
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| E.4 | Principal exclusion criteria |
The following criteria should be checked at the time of study entry. If any apply, the subject must not be included in the study:
-Acute disease at the time of enrolment (acute disease is de-fined as the presence of a moderate or severe illness with or without fever). All vaccines can be administered to persons with a minor illness such as diarrhea, mild upper respiratory infection with or without low-grade febrile illness, i.e. axillary temperature < 37.5°C).
-Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests.
-Anemia defined as: hemoglobin < 5.0 g/dL or hemoglobin < 8 g/dL associated with clinical signs of heart failure or severe respiratory distress.
-Major congenital defects.
-History of allergic reactions, significant IgE-mediated events or anaphylaxis to previous immunizations.
-Children with a past history of a neurological disorder or atypical febrile seizure (a febrile seizure is atypical if it meets one of the following criteria: not associated with fever; lasts > 5 minutes; focal (not generalized); followed by transient or persistent neurological abnormality; occurs in a child < 6 months of age).
Children with malnutrition requiring hospital admission.
Children currently meeting the criteria for HIV disease of Stage III or Stage IV severity as defined by the World Health Organi-zation [WHO, 2005]. NB: a previous history of having Stage III or Stage IV HIV disease is NOT an exclusion criterion.
-History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
-Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to a drug or vaccine that is not licensed for that indication (by one of the following authorities: FDA or EU member state or WHO [with respect to prequalification]) with the exception of studies with the objective of improving the drug treatment or clinical management of severe malaria disease.
-Use of a drug or vaccine that is not approved for that indication (by one of the following authorities: FDA or EU member state or WHO [with respect to prequalification]) other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period.
-Previous participation in any other malaria vaccine trial.
-Receipt of a vaccine within the preceding 7 days
-Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trial.
-Any other findings that the investigator feels would result in data collected being incomplete or of poor quality. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For a primary schedule, in children aged 6-12 weeks at the time of Dose 1, the occurrence of cases of malaria meeting the primary case definition for clinical malaria disease.
For a primary schedule, in children aged 5-17 months at the time of Dose 1, the occurrence of cases of malaria meeting the primary case definition for clinical malaria disease.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For both primary endpoints:
Over a period starting 14 days post Dose 3 for 12 months, or until the time at which 450 subjects experience a case, whichever occurs later. |
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| E.5.2 | Secondary end point(s) |
For a primary schedule (pooled with and without a boost), the occurrence of severe malaria disease meeting the primary and secondary case definitions
-For a primary schedule with and without boost, the occurrence of severe malaria disease meeting the primary and secondary case definitions
-For a primary schedule with and without boost, the occurrene of incident severe anemia and malaria hospitalization meeting the primary and secondary case definitions
-Duration of efficacy of a primary course: for a primary schedule without boost, the occurrence of clinical malaria disease meeting the primary case definition
-Role of a booster: for a primary schedule with and without boost, the occurrence of clinical malaria meeting the primary case definition
-Efficacy under different transmission settings: for each site, for a primary schedule with and without a boost, the occurrence of clinical malaria disease meeting the primary case definition
-For a primary schedule with and without boost, the occurrence of clinical malaria disease meeting the secondary case definitions
-Efficacy against prevalence of parasitemia
-Efficacy against prevalence of moderate and severe anemia
-Safety of a primary course: SAEs (for each age category)
-Safety of a primary course: solicited symptoms (for each age category)
-Safety of a primary course: unsolicited symptoms related to vaccination or leading to withdrawal (for each age category)
-Safety of a booster dose: SAEs (for each age category)
-Safety of a booster dose: solicited symptoms (for each age category)
-Safety of a booster dose: unsolicited symptoms (for each age category)
-Immunogenicity of a primary course: anti-CS and anti-HBs antibody titers (for each age category)
-Immunogenicity of booster dose: anti-CS and anti-HBs antibody titers (for each age category)
-Immunogenicity of polio serotypes 1, 2 and 3: percentage of subjects with seroprotective levels of anti-polio 1, 2, 3 antibodies (in a subset of African children whose age at first dose will be 6-12 weeks)
-Efficacy against other serious illness: occurrence of other serious illness meeting the primary and secondary case definitions
-Efficacy against fatal malaria and all-cause mortality: occurrence of fatal malaria (meeting the case definitions) and all-cause mortality
-Effect on growth: to compare the height/length for age z-score, weight for age z-score and the mid arm circumference for age z-score
-Gender-specific efficacy: in male and female children, for a primary schedule with and without a boost the occurrence of clinical malaria disease meeting the primary case definition
-Immunological correlates of protection: in cases and non-cases of malaria disease, CS-antibody titers
-In HIV-infected children, for each age category, for a primary schedule with and without a boost, the occurrence of SAEs
-In HIV-infected children, for each age category, for a primary schedule and a booster dose, the occurrence of unsolicited symptoms related to vaccination or leading to withdrawal
-In HIV-infected children, for each age category, for a primary schedule with and without a boost, the anti-CS and anti-HBs antibody titers
-In low weight for age children and in very low weight for age children, for each age category, for a primary schedule with and without a boost, the occurrence of SAEs
-In low weight for age children and in very low weight for age children, for each age category, for a primary schedule and a boost, the occurrence of unsolicited symptoms related to vaccination or leading to withdrawal
-In low weight for age children and in very low weight for age children, for each age category, for a primary schedule with and without a boost, the anti-CS and anti-HBs antibody titers
-In each of at least three study centers, the occurrence of clinical malaria disease meeting the primary and secondary case definitions for clinical malaria
-Pooled across at least three study centers, the occurrence of clinical malaria disease meeting the primary and secondary case definitions for clinical malaria.
-Pooled across at least three study centers, the occurrence of:
---severe malaria meeting the primary and secondary case definitions for severe malaria
---malaria hospitalization meeting the primary and secondary case definitions for malaria hospitalization
---all-cause mortality and fatal malaria meeting the primary and secondary case definitions
---all-medical hospitalization meeting the primary case definition.
---pneumonia meeting the primary and secondary case definitions
---sepsis meeting the primary case definition
-Pooled across all participating study centers, the presence of parasitemia
-Pooled across all participating study centers, the presence of moderate and severe anemia
-In all participating study centers, the occurrence of SAEs
-In a subset of subjects, the anti-CS antibody titers
-In all subjects at all participating study centers, to compare the height for age z-score |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All secondary endpoints were evaluated at different timepoints and/or over different time periods (maximum range: between administration of Dose 1 and study end) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Burkina Faso |
| Gabon |
| Ghana |
| Kenya |
| Malawi |
| Mozambique |
| Tanzania, United Republic of |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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