Malaria,FalciparumPhase 3RTSS-SMCNCT03143218
Seasonal Malaria Vaccination (RTS,S/AS01) and Seasonal Malaria Chemoprevention (SP/AQ)
A Phase 3 study testing RABIPUR®, RTS,S/AS01 and SMC with SP+AQ in people with Malaria,Falciparum and Children, Only, run by London School of Hygiene and Tropical Medicine at 2 sites in 2 countries.
Trial summary
A double-blind, individual randomised trial will be undertaken in 6000 children under the age of five years living in areas of Burkina Faso or Mali where the transmission of malaria is intense and highly seasonal to determine whether the malaria vaccine RTS,S/AS01 is (a) as effective as SMC with SP + AQ in preventing… Read more about this study
- Who is it for?
- Ages 5 to 17 months
- Conditions the study is for
- Malaria,Falciparum, Children, Only
- What is being tested?
- RABIPUR®, RTS,S/AS01 and SMC with SP+AQ
- Type of treatment
- Vaccines
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 5,920 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 17 Apr 2017to 31 Mar 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 to 17 months
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- The child is a permanent resident of the study area and likely to remain a resident for the duration of the trial
- The child is 5 - 17 months of age at the time of first vaccination
- A parent or legally recognised guardian provides informed consent for the child to join the trial
Who cannot join
- The child is a transient resident in the study area
- The child is in care
- The age of the child is outside the stipulated range
- The child has a history of an adverse reaction to SP or AQ
- The child has a serious underlying illness, including known HIV infection, unless this is well controlled by treatment, or severe malnutrition (weight for age or mid arm circumference Z scores < 3 SD)
- The child is known to have an immune deficiency disease or is receiving an immunosuppressive drug
Show all 9Show fewer
- The child has previously received a malaria vaccine.
- The child is enrolled in another malaria intervention trial
- The parents or guardians do not provide informed consent
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
Burkina Faso1 site
Institut de Recherche en Sciences de la Santé, Direction Régionale de l'Ouest
Ouagadougou
About this study
Official title: A Phase IIIB Comparative Trial of Seasonal Vaccination With the Malaria Vaccine RTS,S/AS01, Seasonal Malaria Chemoprevention and of the Two Interventions Combined
A double-blind, individual randomised trial will be undertaken in 6000 children under the age of five years living in areas of Burkina Faso or Mali where the transmission of malaria is intense and highly seasonal to determine whether the malaria vaccine RTS,S/AS01 is (a) as effective as SMC with SP + AQ in preventing clinical malaria (b) provides additional, useful protection when given together with SMC. The primary trial end-point will be the incidence of clinical episodes of malaria detected by passive case detection.
Read the detailed description
The RTS,S/AS01 malaria vaccine is a recombinant protein vaccine in which the fusion protein RTS (containing parts of the circumsporozoite protein (CSP) of Plasmodium falciparum fused to hepatitis B surface antigen (HBsAg)) is co-expressed in yeast together with free HBsAg (S) to form a virus like particle (RTS,S); it is given with the powerful adjuvant AS01. RTS,S/AS01 induces a strong antibody response to the P. falciparum CSP and high titres of anti-CSP antibody are associated with protection. Following a long process of development, a phase 3 study of RTS,S/AS01 conducted in 15,439 children in 7 countries in Africa showed that three doses of RTS,S/AS01 given with a one month interval between doses, followed by a fourth dose 18 months post dose 3, gave 36.5 % [95% CI 31,41%] protection against clinical attacks of malaria when given to young children aged 5-17 months who were followed for 48 months; efficacy was less when given to infants at the age of 6-12 weeks. RTS,S/AS01 provides a high level of protection during the first three months after vaccination, modelled to be about 70% in the phase 3 trial, a level of initial efficacy similar to that observed in an earlier phase 2 trial in Gambian adults. However, efficacy wanes progressively over the following months. A subsequent dose given 18 months after the primary series restores some but not all of the efficacy seen immediately after the primary series. In July 2015, the European Medicines Agency reviewed efficacy and safety data on RTS.S/AS01 and concluded that the risk benefit balance favoured the vaccine and gave a positive opinion on its use in children aged 6 weeks to 17 months. The World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) committee reviewed the vaccine's efficacy and safety in October 2015 and made a number of recommendations on its further evaluation. These included the pilot implementation of RTS,S/AS01 in children aged 5-17 months in 3-5 settings with moderate-to-high malaria transmission intensity, with a preference for areas where SMC is not being delivered, and evaluation of alternative approaches to deployment of the vaccine. Recent evidence from challenge studies conducted in American adult volunteers suggests that a higher level of protection can be obtained when the third dose of the priming schedule is reduced to one fifth of the usual amount and delayed until approximately 6 months post dose 2, and when a reduced dose is used for boosting. In these studies, a vaccine efficacy of 86% was achieved three weeks following priming and 90% efficacy following boosting with a fractional dose. This encouraging result is now being followed in further studies.
SMC involves monthly administration of an antimalarial drug or drug combination in a full therapeutic course to children on three of four occasions during the period of highest risk of malaria infection. Studies undertaken in several countries in West Africa, including Burkina Faso and Mali, have shown that SMC with sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) is highly effective in areas where the transmission of malaria is markedly seasonal, reducing the incidence of severe and uncomplicated malaria by up to 80%. SMC with a combination of SP and AQ is safe, with no serious drug related adverse event being reported after administration of over 800,000 courses in Senegal. Recent studies have defined the areas where SMC would be an appropriate intervention based on the seasonality and incidence of malaria. These include most of the Sahel and sub-Sahel, population approximately 200 million, and possibly other areas in southern and eastern Africa. A Technical Expert Group of the WHO reviewed all the available evidence on the efficacy and safety of SMC in May 2011 and recommended SMC with SP+AQ in areas of the Sahel and sub-Sahel with highly seasonal transmission. This recommendation was endorsed by the WHO Malaria Policy Advisory Committee (MPAC) in February 2012. Most countries in the Sahel and sub-Sahel region have incorporated SMC, along with other malaria control interventions in their strategic malaria control plan and the implementation of SMC at scale is in progress in many countries in this region through the UNITAID supported SMC ACCESS programme and the support of other major donor organisations. Preliminary evaluation suggests that SMC is providing about 50% protection against clinical malaria when delivered through a national programme (http://www.malariaconsortium.org/pages/access-smc.htm).
SMC is effective but its delivery is demanding on the recipient and provider, requiring four contacts each malaria transmission season if anti-malarials are given to mothers to administer at home and 12 contacts if directly observed treatment is employed. In addition, SMC is threatened by the emergence of resistance to SP and AQ and there are currently no other combinations of licensed antimalarials that could be used to replace them. It is likely to be 5-10 years before novel antimalarials under development could be deployed for SMC. In contrast to SMC, seasonal vaccination with RTS,S/AS01 would require only one visit each transmission season after priming. RTS,S/AS01 may be a little less effective than SMC during the malaria transmission season but this may be balanced by provision of protection during the dry season, when some malaria transmission still occurs and when SMC would provide no benefit. There is, therefore, a need for a comparative study of these two interventions. In some areas where SMC is currently being deployed, and other malaria control interventions such as long-lasting insecticide treated nets used widely, the incidence of malaria in young children remains high (0.4 episodes per year in children under the age of five years in SMC recipients in Burkina Faso). Thus, determining whether RTS,S/AS01 would provide added, useful protection to SMC in such situations is also important. It might also be able to protect some children who, because of side effects, are unable or unwilling to take SMC.
Although the European Medicines Agency has given a positive opinion on RTS,S/AS01, it is not yet certain how this partially effective malaria vaccine can be used most effectively. Three, large-scale pilot implementation studies are being planned by WHO but it is unlikely that, following WHO recommendations, any of these will be conducted in a country where SMC is being delivered. The WHO recommendations on RTS,S/AS01 indicate the need for research on alternative approaches to the delivery of this vaccine. Exploration of the potential of the vaccine to prevent seasonal malaria, taking advantage of its high but rapidly waning efficacy, meets this recommendation and is, therefore, timely.
- Conditions
- Malaria,Falciparum, Children, Only
- Being tested
- RABIPUR®, RTS,S/AS01, SMC with SP+AQ, SMC placebo
- Keywords
- Malaria, Seasonal vaccination, Seasonal chemoprevention
- Medical subject headings
- Malaria, Falciparum, Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RABIPUR®Biological
Year 1 (2017) Three doses of rabies vaccine (April, May, June) Year 2 and 3 (2018/19) One dose of Hepatitis A vaccine (June)
RTS,S/AS01Biological
Year 1 (2017) Three doses of RTSS/AS01 (April, May, June) Year 2 and 3 (2018/19) One booster dose of RTSS/AS01 (June)
SMC with SP+AQDrug
Year 1, 2 and 3(2017/18/19) Four cycles of SMC (SP+AQ) during the malaria transmission season One cycle of SMC for children above one year of age consisting of sulphadoxine - pyrimethamin (SP) 500mg/25 mg, and amodiaquine (AQ) 150mg on day 1, and AQ 150mg on days 2 and 3. Infants will receive half of these doses.
SMC placeboDrug
Year 1, 2 and 3(2017/18/19) Four cycles of SMC placebo during the malaria transmission season
| Study group | Role | What they receive |
|---|---|---|
| SMC with SP+AQ | Active comparator | Administration of RABIPUR® in Year 1 and Hepatitis A vaccine in Year 2 and 3, followed by 4 cycles of SMC with sulphadoxine/pyrimethamine plus amodiaquine in Year 1,2 and 3. Receives: Biological: RABIPUR®; Drug: SMC with SP+AQ |
| RTS,S/AS01 | Active comparator | Administration of the malaria vaccine RTS,S/AS01 followed by 4 cycles of SMC with placebo in Year 1,2 and 3. Receives: Biological: RTS,S/AS01; Drug: SMC placebo |
| RTS,S/AS01 PLUS SMC with SP+AQ | Active comparator | Administration of the malaria vaccine RTS,S/AS01 followed by 4 cycles of SMC with sulphadoxine/pyrimethamine plus amodiaquine in Year 1,2 and 3. Receives: Biological: RTS,S/AS01; Drug: SMC with SP+AQ |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of Clinical Episodes of Malaria
Passive surveillance to detect episode of fever (temperature > 37.5 C), or a history of fever within the past 48 hours, that is severe enough to require treatment at a health centre and which is accompanied by a positive blood film with a parasite density of 5,000 per µl or more
Measured: Passive surveillance of clinical episodes of malaria within the study area starting from the date of the first dose of study vaccines (April/May 2017) until 31st March 2020- a total of 36 months.
Secondary outcomes (9)
Clinical Episodes of Uncomplicated Febrile Illness
Passive and active surveillance to detect cases with temperature > 37.5o C), or a history of fever within the past 48 hours, with a positive blood film (any level of asexual parasitaemia) or a positive rapid diagnostic test (RDT) for malaria
Measured: Passive surveillance in all health centers within the study area, active surveillance in a sub set of study children starting July 2017 till April 2020.
Hospital Admissions With Malaria, Including Severe Malaria
Hospital admissions with malaria, including cases of severe malaria which meet WHO criteria for a diagnosis of severe malaria.
Measured: Through study completion (30 months), each child admitted in a study hospital will be treated and monitored until complete cure or death (a period of 3 years). Documentation of each hospital admission according to ICH-GCP.
Prevalence of Malaria Infection Not Severe Enough to Warrant a Clinic Visit
Active surveillance of malaria at household level to assess the prevalence of malaria infection not severe enough to warrant a clinic visit detected in a subset of randomly selected children.
Measured: Weekly home visits through study completion from July 2017 - April 2020 to screen study children for malaria.
Prevalence of Malaria Parasitaemia, Including Gametocytaemia and the Prevalence of Moderate and Severe Anemia and Malnutrition
The prevalence of malaria parasitaemia, including gametocytaemia, moderate and severe anaemia and malnutrition at the end of the malaria transmission season
Measured: Blood sample collection during 2-week cross sectional survey at the end of each malaria transmission season.
Serious Adverse Events (SAEs)
Serious adverse events (SAEs), including any deaths, occurring at any time during the study with special reference to any cases of meningitis and cerebral malaria (WHO case definition)
Measured: Through study completion (for 30 months), each SAE will be treated and documented according to ICH-GCP.
Immune Response to the Vaccine (Anti-CSP Antibody Concentrations)
After priming and after each booster dose, determined in a sub-sample of children
Measured: Blood sample collection prior to 1st dose of vaccine and 1 month after 3rd dose of the primary series of vaccination. In years 2 and 3 blood will be collected before the booster dose and 1 month after administration of the 4th (and 5th) vaccine dose.
Drug Resistance to SP and AQ
The presence of molecular markers of resistance to SP and AQ in parasite positive samples
Measured: Blood sample collection during the 2-week cross sectional survey conducted at the end of malaria transmission season in 2019.
Prevalence of Malaria Parasitaemia in School Aged Children
The prevalence of malaria parasitaemia at the end of the malaria transmission season in school-age children resident in the study areas, to determine overall malaria transmission
Measured: Blood sample collection during the 2-week cross sectional survey at the end of the malaria transmission season in Year 2 and 3 (November 2018/19).
SP+AQ Drug Sensitivity
The 28-day treatment outcome in children with asymptomatic malaria parasitaemia treated with SP+AQ.
Measured: Children with asymptomatic malaria parasitaemia identified during the final cross-sectional survey (November 2019), treated with a full course of SP+AQ over 3 days and followed for 28 days.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 May 2017
- Study start17 Apr 2017
- Primary completion31 Mar 2020
- Study completion31 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for Malaria,FalciparumStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A double-blind, individually randomised trial to compare the incidence of clinical episodes of malaria across three study arms: 1. Seasonal vaccination with the malaria vaccine RTS,S/AS01 2. Seasonal malaria chemoprevention with SP/AQ 3. Combination of these two interventions
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 5,920 participants (actual)
Sponsor and investigators
- Lead sponsor
- London School of Hygiene and Tropical Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Malaria Research and Training Center, Bamako, Mali, Institut de Recherche en Sciences de la Sante, Burkina Faso
- Responsible party
- Principal investigator, Brian Greenwood, London School of Hygiene and Tropical Medicine
- Investigators
- Alassane Dicko, Professor, Study director, Malaria Research & Training Center, BamakoJean Bosco Ouedraogo, Professor, Study director, Institut de Recherche en Sciences de la Santé, Direction Régionale de l'Ouest (IRSS-DRO)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03143218
- Sponsor's protocol ID
- ITDCZJ29 - Greenwood
- Acronym
- RTSS-SMC
- Status last verified
- Mar 2022
- First submitted
- 22 Mar 2017
- Last updated
- 7 Apr 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be made available through the LSHTM Data Compass system
Publications
Cohen J, Nussenzweig V, Nussenzweig R, Vekemans J, Leach A. From the circumsporozoite protein to the RTS, S/AS candidate vaccine. Hum Vaccin. 2010 Jan;6(1):90-6. doi: 10.4161/hv.6.1.9677. Epub 2010 Jan 30.
PubMed 19806009White MT, Verity R, Griffin JT, Asante KP, Owusu-Agyei S, Greenwood B, Drakeley C, Gesase S, Lusingu J, Ansong D, Adjei S, Agbenyega T, Ogutu B, Otieno L, Otieno W, Agnandji ST, Lell B, Kremsner P, Hoffman I, Martinson F, Kamthunzu P, Tinto H, Valea I, Sorgho H, Oneko M, Otieno K, Hamel MJ, Salim N, Mtoro A, Abdulla S, Aide P, Sacarlal J, Aponte JJ, Njuguna P, Marsh K, Bejon P, Riley EM, Ghani AC. Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial. Lancet Infect Dis. 2015 Dec;15(12):1450-8. doi: 10.1016/S1473-3099(15)00239-X. Epub 2015 Sep 2.
PubMed 26342424RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015 Jul 4;386(9988):31-45. doi: 10.1016/S0140-6736(15)60721-8. Epub 2015 Apr 23.
PubMed 25913272Bojang KA, Milligan PJ, Pinder M, Vigneron L, Alloueche A, Kester KE, Ballou WR, Conway DJ, Reece WH, Gothard P, Yamuah L, Delchambre M, Voss G, Greenwood BM, Hill A, McAdam KP, Tornieporth N, Cohen JD, Doherty T; RTS, S Malaria Vaccine Trial Team. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet. 2001 Dec 8;358(9297):1927-34. doi: 10.1016/S0140-6736(01)06957-4.
PubMed 11747915Regules JA, Cicatelli SB, Bennett JW, Paolino KM, Twomey PS, Moon JE, Kathcart AK, Hauns KD, Komisar JL, Qabar AN, Davidson SA, Dutta S, Griffith ME, Magee CD, Wojnarski M, Livezey JR, Kress AT, Waterman PE, Jongert E, Wille-Reece U, Volkmuth W, Emerling D, Robinson WH, Lievens M, Morelle D, Lee CK, Yassin-Rajkumar B, Weltzin R, Cohen J, Paris RM, Waters NC, Birkett AJ, Kaslow DC, Ballou WR, Ockenhouse CF, Vekemans J. Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study. J Infect Dis. 2016 Sep 1;214(5):762-71. doi: 10.1093/infdis/jiw237. Epub 2016 Jun 13.
PubMed 27296848Wilson AL; IPTc Taskforce. A systematic review and meta-analysis of the efficacy and safety of intermittent preventive treatment of malaria in children (IPTc). PLoS One. 2011 Feb 14;6(2):e16976. doi: 10.1371/journal.pone.0016976.
PubMed 21340029Dicko A, Diallo AI, Tembine I, Dicko Y, Dara N, Sidibe Y, Santara G, Diawara H, Conare T, Djimde A, Chandramohan D, Cousens S, Milligan PJ, Diallo DA, Doumbo OK, Greenwood B. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial. PLoS Med. 2011 Feb 1;8(2):e1000407. doi: 10.1371/journal.pmed.1000407.
PubMed 21304923Konate AT, Yaro JB, Ouedraogo AZ, Diarra A, Gansane A, Soulama I, Kangoye DT, Kabore Y, Ouedraogo E, Ouedraogo A, Tiono AB, Ouedraogo IN, Chandramohan D, Cousens S, Milligan PJ, Sirima SB, Greenwood B, Diallo DA. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial. PLoS Med. 2011 Feb 1;8(2):e1000408. doi: 10.1371/journal.pmed.1000408.
PubMed 21304925NDiaye JL, Cisse B, Ba EH, Gomis JF, Ndour CT, Molez JF, Fall FB, Sokhna C, Faye B, Kouevijdin E, Niane FK, Cairns M, Trape JF, Rogier C, Gaye O, Greenwood BM, Milligan PJ. Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial. PLoS One. 2016 Oct 20;11(10):e0162563. doi: 10.1371/journal.pone.0162563. eCollection 2016.
PubMed 27764102Cairns M, Roca-Feltrer A, Garske T, Wilson AL, Diallo D, Milligan PJ, Ghani AC, Greenwood BM. Estimating the potential public health impact of seasonal malaria chemoprevention in African children. Nat Commun. 2012 Jun 6;3:881. doi: 10.1038/ncomms1879.
PubMed 22673908Penny MA, Verity R, Bever CA, Sauboin C, Galactionova K, Flasche S, White MT, Wenger EA, Van de Velde N, Pemberton-Ross P, Griffin JT, Smith TA, Eckhoff PA, Muhib F, Jit M, Ghani AC. Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models. Lancet. 2016 Jan 23;387(10016):367-375. doi: 10.1016/S0140-6736(15)00725-4. Epub 2015 Nov 6.
PubMed 26549466Neafsey DE, Juraska M, Bedford T, Benkeser D, Valim C, Griggs A, Lievens M, Abdulla S, Adjei S, Agbenyega T, Agnandji ST, Aide P, Anderson S, Ansong D, Aponte JJ, Asante KP, Bejon P, Birkett AJ, Bruls M, Connolly KM, D'Alessandro U, Dobano C, Gesase S, Greenwood B, Grimsby J, Tinto H, Hamel MJ, Hoffman I, Kamthunzi P, Kariuki S, Kremsner PG, Leach A, Lell B, Lennon NJ, Lusingu J, Marsh K, Martinson F, Molel JT, Moss EL, Njuguna P, Ockenhouse CF, Ogutu BR, Otieno W, Otieno L, Otieno K, Owusu-Agyei S, Park DJ, Pelle K, Robbins D, Russ C, Ryan EM, Sacarlal J, Sogoloff B, Sorgho H, Tanner M, Theander T, Valea I, Volkman SK, Yu Q, Lapierre D, Birren BW, Gilbert PB, Wirth DF. Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine. N Engl J Med. 2015 Nov 19;373(21):2025-2037. doi: 10.1056/NEJMoa1505819. Epub 2015 Oct 21.
PubMed 26488565Swysen C, Vekemans J, Bruls M, Oyakhirome S, Drakeley C, Kremsner P, Greenwood B, Ofori-Anyinam O, Okech B, Villafana T, Carter T, Savarese B, Duse A, Reijman A, Ingram C, Frean J, Ogutu B; Clinical Trials Partnership Committee. Development of standardized laboratory methods and quality processes for a phase III study of the RTS, S/AS01 candidate malaria vaccine. Malar J. 2011 Aug 4;10:223. doi: 10.1186/1475-2875-10-223.
PubMed 21816032Plowe CV, Djimde A, Bouare M, Doumbo O, Wellems TE. Pyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase: polymerase chain reaction methods for surveillance in Africa. Am J Trop Med Hyg. 1995 Jun;52(6):565-8. doi: 10.4269/ajtmh.1995.52.565.
PubMed 7611566Djimde A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourte Y, Coulibaly D, Dicko A, Su XZ, Nomura T, Fidock DA, Wellems TE, Plowe CV. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med. 2001 Jan 25;344(4):257-63. doi: 10.1056/NEJM200101253440403.
PubMed 11172152
Study at a glance
From the registry record, last updated by the sponsor on 7 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase IIIB Comparative Trial of Seasonal Vaccination With the Malaria Vaccine RTS,S/AS01, Seasonal Malaria Chemoprevention and of the Two Interventions Combined
- ClinicalTrials.gov ID
- NCT03143218
- Acronym / sponsor ID
- RTSS-SMC / ITDCZJ29 - Greenwood
- Conditions
- Malaria,Falciparum, Children, Only
- Keywords
- Malaria, Seasonal vaccination, Seasonal chemoprevention
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5,920 participants (actual)
- Lead sponsor
- London School of Hygiene and Tropical MedicineUniversity, hospital or other
- Collaborators
- Malaria Research and Training Center, Bamako, Mali, Institut de Recherche en Sciences de la Sante, Burkina Faso
- Study start
- 17 Apr 2017 (actual)
- Primary completion
- 31 Mar 2020 (actual)
- Study completion
- 31 Mar 2020 (actual)
- First posted
- 8 May 2017 (actual)
- Results
- Posted 28 Jan 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A double-blind, individual randomised trial will be undertaken in 6000 children under the age of five years living in areas of Burkina Faso or Mali where the transmission of malaria is intense and highly seasonal to determine whether the malaria vaccine RTS,S/AS01 is (a) as effective as SMC with SP + AQ in preventing clinical malaria (b) provides additional, useful protection when given together with SMC. The primary trial end-point will be the incidence of clinical episodes of malaria detected by passive case detection.
Detailed description
The RTS,S/AS01 malaria vaccine is a recombinant protein vaccine in which the fusion protein RTS (containing parts of the circumsporozoite protein (CSP) of Plasmodium falciparum fused to hepatitis B surface antigen (HBsAg)) is co-expressed in yeast together with free HBsAg (S) to form a virus like particle (RTS,S); it is given with the powerful adjuvant AS01. RTS,S/AS01 induces a strong antibody response to the P. falciparum CSP and high titres of anti-CSP antibody are associated with protection. Following a long process of development, a phase 3 study of RTS,S/AS01 conducted in 15,439 children in 7 countries in Africa showed that three doses of RTS,S/AS01 given with a one month interval between doses, followed by a fourth dose 18 months post dose 3, gave 36.5 % [95% CI 31,41%] protection against clinical attacks of malaria when given to young children aged 5-17 months who were followed for 48 months; efficacy was less when given to infants at the age of 6-12 weeks. RTS,S/AS01 provides a high level of protection during the first three months after vaccination, modelled to be about 70% in the phase 3 trial, a level of initial efficacy similar to that observed in an earlier phase 2 trial in Gambian adults. However, efficacy wanes progressively over the following months. A subsequent dose given 18 months after the primary series restores some but not all of the efficacy seen immediately after the primary series. In July 2015, the European Medicines Agency reviewed efficacy and safety data on RTS.S/AS01 and concluded that the risk benefit balance favoured the vaccine and gave a positive opinion on its use in children aged 6 weeks to 17 months. The World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) committee reviewed the vaccine's efficacy and safety in October 2015 and made a number of recommendations on its further evaluation. These included the pilot implementation of RTS,S/AS01 in children aged 5-17 months in 3-5 settings with moderate-to-high malaria transmission intensity, with a preference for areas where SMC is not being delivered, and evaluation of alternative approaches to deployment of the vaccine. Recent evidence from challenge studies conducted in American adult volunteers suggests that a higher level of protection can be obtained when the third dose of the priming schedule is reduced to one fifth of the usual amount and delayed until approximately 6 months post dose 2, and when a reduced dose is used for boosting. In these studies, a vaccine efficacy of 86% was achieved three weeks following priming and 90% efficacy following boosting with a fractional dose. This encouraging result is now being followed in further studies.
SMC involves monthly administration of an antimalarial drug or drug combination in a full therapeutic course to children on three of four occasions during the period of highest risk of malaria infection. Studies undertaken in several countries in West Africa, including Burkina Faso and Mali, have shown that SMC with sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) is highly effective in areas where the transmission of malaria is markedly seasonal, reducing the incidence of severe and uncomplicated malaria by up to 80%. SMC with a combination of SP and AQ is safe, with no serious drug related adverse event being reported after administration of over 800,000 courses in Senegal. Recent studies have defined the areas where SMC would be an appropriate intervention based on the seasonality and incidence of malaria. These include most of the Sahel and sub-Sahel, population approximately 200 million, and possibly other areas in southern and eastern Africa. A Technical Expert Group of the WHO reviewed all the available evidence on the efficacy and safety of SMC in May 2011 and recommended SMC with SP+AQ in areas of the Sahel and sub-Sahel with highly seasonal transmission. This recommendation was endorsed by the WHO Malaria Policy Advisory Committee (MPAC) in February 2012. Most countries in the Sahel and sub-Sahel region have incorporated SMC, along with other malaria control interventions in their strategic malaria control plan and the implementation of SMC at scale is in progress in many countries in this region through the UNITAID supported SMC ACCESS programme and the support of other major donor organisations. Preliminary evaluation suggests that SMC is providing about 50% protection against clinical malaria when delivered through a national programme (http://www.malariaconsortium.org/pages/access-smc.htm).
SMC is effective but its delivery is demanding on the recipient and provider, requiring four contacts each malaria transmission season if anti-malarials are given to mothers to administer at home and 12 contacts if directly observed treatment is employed. In addition, SMC is threatened by the emergence of resistance to SP and AQ and there are currently no other combinations of licensed antimalarials that could be used to replace them. It is likely to be 5-10 years before novel antimalarials under development could be deployed for SMC. In contrast to SMC, seasonal vaccination with RTS,S/AS01 would require only one visit each transmission season after priming. RTS,S/AS01 may be a little less effective than SMC during the malaria transmission season but this may be balanced by provision of protection during the dry season, when some malaria transmission still occurs and when SMC would provide no benefit. There is, therefore, a need for a comparative study of these two interventions. In some areas where SMC is currently being deployed, and other malaria control interventions such as long-lasting insecticide treated nets used widely, the incidence of malaria in young children remains high (0.4 episodes per year in children under the age of five years in SMC recipients in Burkina Faso). Thus, determining whether RTS,S/AS01 would provide added, useful protection to SMC in such situations is also important. It might also be able to protect some children who, because of side effects, are unable or unwilling to take SMC.
Although the European Medicines Agency has given a positive opinion on RTS,S/AS01, it is not yet certain how this partially effective malaria vaccine can be used most effectively. Three, large-scale pilot implementation studies are being planned by WHO but it is unlikely that, following WHO recommendations, any of these will be conducted in a country where SMC is being delivered. The WHO recommendations on RTS,S/AS01 indicate the need for research on alternative approaches to the delivery of this vaccine. Exploration of the potential of the vaccine to prevent seasonal malaria, taking advantage of its high but rapidly waning efficacy, meets this recommendation and is, therefore, timely.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
- Model description
- A double-blind, individually randomised trial to compare the incidence of clinical episodes of malaria across three study arms: 1. Seasonal vaccination with the malaria vaccine RTS,S/AS01 2. Seasonal malaria chemoprevention with SP/AQ 3. Combination of these two interventions
| Arm | Type | Receives |
|---|---|---|
| SMC with SP+AQ | Active comparator | Biological: RABIPUR®, Drug: SMC with SP+AQAdministration of RABIPUR® in Year 1 and Hepatitis A vaccine in Year 2 and 3, followed by 4 cycles of SMC with sulphadoxine/pyrimethamine plus amodiaquine in Year 1,2 and 3. |
| RTS,S/AS01 | Active comparator | Biological: RTS,S/AS01, Drug: SMC placeboAdministration of the malaria vaccine RTS,S/AS01 followed by 4 cycles of SMC with placebo in Year 1,2 and 3. |
| RTS,S/AS01 PLUS SMC with SP+AQ | Active comparator | Biological: RTS,S/AS01, Drug: SMC with SP+AQAdministration of the malaria vaccine RTS,S/AS01 followed by 4 cycles of SMC with sulphadoxine/pyrimethamine plus amodiaquine in Year 1,2 and 3. |
Who may qualify
- Ages
- 5 to 17 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- The child is a permanent resident of the study area and likely to remain a resident for the duration of the trial
- The child is 5 - 17 months of age at the time of first vaccination
- A parent or legally recognised guardian provides informed consent for the child to join the trial
Key exclusion criteria (9 listed)
- The child is a transient resident in the study area
- The child is in care
- The age of the child is outside the stipulated range
- The child has a history of an adverse reaction to SP or AQ
- The child has a serious underlying illness, including known HIV infection, unless this is well controlled by treatment, or severe malnutrition (weight for age or mid arm circumference Z scores < 3 SD)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RABIPUR®Year 1 (2017) Three doses of rabies vaccine (April, May, June) Year 2 and 3 (2018/19) One dose of Hepatitis A vaccine (June) | Biological | SMC with SP+AQ |
| RTS,S/AS01Year 1 (2017) Three doses of RTSS/AS01 (April, May, June) Year 2 and 3 (2018/19) One booster dose of RTSS/AS01 (June) | Biological | RTS,S/AS01, RTS,S/AS01 PLUS SMC with SP+AQ |
| SMC with SP+AQYear 1, 2 and 3(2017/18/19) Four cycles of SMC (SP+AQ) during the malaria transmission season One cycle of SMC for children above one year of age consisting of sulphadoxine - pyrimethamin (SP) 500mg/25 mg, and amodiaquine (AQ) 150mg on day 1, and AQ 150mg on days 2 and 3. Infants will receive half of these doses. | Drug | RTS,S/AS01 PLUS SMC with SP+AQ, SMC with SP+AQ |
| SMC placeboYear 1, 2 and 3(2017/18/19) Four cycles of SMC placebo during the malaria transmission season | Drug | RTS,S/AS01 |
Primary outcome
Incidence of Clinical Episodes of Malaria
Time frame: Passive surveillance of clinical episodes of malaria within the study area starting from the date of the first dose of study vaccines (April/May 2017) until 31st March 2020- a total of 36 months.
Passive surveillance to detect episode of fever (temperature > 37.5 C), or a history of fever within the past 48 hours, that is severe enough to require treatment at a health centre and which is accompanied by a positive blood film with a parasite density of 5,000 per µl or more
9 secondary outcomes
Clinical Episodes of Uncomplicated Febrile Illness
Time frame: Passive surveillance in all health centers within the study area, active surveillance in a sub set of study children starting July 2017 till April 2020.
Hospital Admissions With Malaria, Including Severe Malaria
Time frame: Through study completion (30 months), each child admitted in a study hospital will be treated and monitored until complete cure or death (a period of 3 years). Documentation of each hospital admission according to ICH-GCP.
Prevalence of Malaria Infection Not Severe Enough to Warrant a Clinic Visit
Time frame: Weekly home visits through study completion from July 2017 - April 2020 to screen study children for malaria.
Prevalence of Malaria Parasitaemia, Including Gametocytaemia and the Prevalence of Moderate and Severe Anemia and Malnutrition
Time frame: Blood sample collection during 2-week cross sectional survey at the end of each malaria transmission season.
Serious Adverse Events (SAEs)
Time frame: Through study completion (for 30 months), each SAE will be treated and documented according to ICH-GCP.
Immune Response to the Vaccine (Anti-CSP Antibody Concentrations)
Time frame: Blood sample collection prior to 1st dose of vaccine and 1 month after 3rd dose of the primary series of vaccination. In years 2 and 3 blood will be collected before the booster dose and 1 month after administration of the 4th (and 5th) vaccine dose.
Drug Resistance to SP and AQ
Time frame: Blood sample collection during the 2-week cross sectional survey conducted at the end of malaria transmission season in 2019.
Prevalence of Malaria Parasitaemia in School Aged Children
Time frame: Blood sample collection during the 2-week cross sectional survey at the end of the malaria transmission season in Year 2 and 3 (November 2018/19).
SP+AQ Drug Sensitivity
Time frame: Children with asymptomatic malaria parasitaemia identified during the final cross-sectional survey (November 2019), treated with a full course of SP+AQ over 3 days and followed for 28 days.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Apr 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19806009Cohen J, Nussenzweig V, Nussenzweig R, Vekemans J, Leach A. From the circumsporozoite protein to the RTS, S/AS candidate vaccine. Hum Vaccin. 2010 Jan;6(1):90-6. doi: 10.4161/hv.6.1.9677. Epub 2010 Jan 30.
- Background: PubMed 26342424White MT, Verity R, Griffin JT, Asante KP, Owusu-Agyei S, Greenwood B, Drakeley C, Gesase S, Lusingu J, Ansong D, Adjei S, Agbenyega T, Ogutu B, Otieno L, Otieno W, Agnandji ST, Lell B, Kremsner P, Hoffman I, Martinson F, Kamthunzu P, Tinto H, Valea I, Sorgho H, Oneko M, Otieno K, Hamel MJ, Salim N, Mtoro A, Abdulla S, Aide P, Sacarlal J, Aponte JJ, Njuguna P, Marsh K, Bejon P, Riley EM, Ghani AC. Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial. Lancet Infect Dis. 2015 Dec;15(12):1450-8. doi: 10.1016/S1473-3099(15)00239-X. Epub 2015 Sep 2.
- Background: PubMed 25913272RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015 Jul 4;386(9988):31-45. doi: 10.1016/S0140-6736(15)60721-8. Epub 2015 Apr 23.
- Background: PubMed 11747915Bojang KA, Milligan PJ, Pinder M, Vigneron L, Alloueche A, Kester KE, Ballou WR, Conway DJ, Reece WH, Gothard P, Yamuah L, Delchambre M, Voss G, Greenwood BM, Hill A, McAdam KP, Tornieporth N, Cohen JD, Doherty T; RTS, S Malaria Vaccine Trial Team. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet. 2001 Dec 8;358(9297):1927-34. doi: 10.1016/S0140-6736(01)06957-4.
- Background: PubMed 27296848Regules JA, Cicatelli SB, Bennett JW, Paolino KM, Twomey PS, Moon JE, Kathcart AK, Hauns KD, Komisar JL, Qabar AN, Davidson SA, Dutta S, Griffith ME, Magee CD, Wojnarski M, Livezey JR, Kress AT, Waterman PE, Jongert E, Wille-Reece U, Volkmuth W, Emerling D, Robinson WH, Lievens M, Morelle D, Lee CK, Yassin-Rajkumar B, Weltzin R, Cohen J, Paris RM, Waters NC, Birkett AJ, Kaslow DC, Ballou WR, Ockenhouse CF, Vekemans J. Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study. J Infect Dis. 2016 Sep 1;214(5):762-71. doi: 10.1093/infdis/jiw237. Epub 2016 Jun 13.
- Background: PubMed 21340029Wilson AL; IPTc Taskforce. A systematic review and meta-analysis of the efficacy and safety of intermittent preventive treatment of malaria in children (IPTc). PLoS One. 2011 Feb 14;6(2):e16976. doi: 10.1371/journal.pone.0016976.
- Background: PubMed 21304923Dicko A, Diallo AI, Tembine I, Dicko Y, Dara N, Sidibe Y, Santara G, Diawara H, Conare T, Djimde A, Chandramohan D, Cousens S, Milligan PJ, Diallo DA, Doumbo OK, Greenwood B. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial. PLoS Med. 2011 Feb 1;8(2):e1000407. doi: 10.1371/journal.pmed.1000407.
- Background: PubMed 21304925Konate AT, Yaro JB, Ouedraogo AZ, Diarra A, Gansane A, Soulama I, Kangoye DT, Kabore Y, Ouedraogo E, Ouedraogo A, Tiono AB, Ouedraogo IN, Chandramohan D, Cousens S, Milligan PJ, Sirima SB, Greenwood B, Diallo DA. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial. PLoS Med. 2011 Feb 1;8(2):e1000408. doi: 10.1371/journal.pmed.1000408.
- Background: PubMed 27764102NDiaye JL, Cisse B, Ba EH, Gomis JF, Ndour CT, Molez JF, Fall FB, Sokhna C, Faye B, Kouevijdin E, Niane FK, Cairns M, Trape JF, Rogier C, Gaye O, Greenwood BM, Milligan PJ. Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial. PLoS One. 2016 Oct 20;11(10):e0162563. doi: 10.1371/journal.pone.0162563. eCollection 2016.
- Background: PubMed 22673908Cairns M, Roca-Feltrer A, Garske T, Wilson AL, Diallo D, Milligan PJ, Ghani AC, Greenwood BM. Estimating the potential public health impact of seasonal malaria chemoprevention in African children. Nat Commun. 2012 Jun 6;3:881. doi: 10.1038/ncomms1879.
- Background: PubMed 26549466Penny MA, Verity R, Bever CA, Sauboin C, Galactionova K, Flasche S, White MT, Wenger EA, Van de Velde N, Pemberton-Ross P, Griffin JT, Smith TA, Eckhoff PA, Muhib F, Jit M, Ghani AC. Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models. Lancet. 2016 Jan 23;387(10016):367-375. doi: 10.1016/S0140-6736(15)00725-4. Epub 2015 Nov 6.
- Background: PubMed 26488565Neafsey DE, Juraska M, Bedford T, Benkeser D, Valim C, Griggs A, Lievens M, Abdulla S, Adjei S, Agbenyega T, Agnandji ST, Aide P, Anderson S, Ansong D, Aponte JJ, Asante KP, Bejon P, Birkett AJ, Bruls M, Connolly KM, D'Alessandro U, Dobano C, Gesase S, Greenwood B, Grimsby J, Tinto H, Hamel MJ, Hoffman I, Kamthunzi P, Kariuki S, Kremsner PG, Leach A, Lell B, Lennon NJ, Lusingu J, Marsh K, Martinson F, Molel JT, Moss EL, Njuguna P, Ockenhouse CF, Ogutu BR, Otieno W, Otieno L, Otieno K, Owusu-Agyei S, Park DJ, Pelle K, Robbins D, Russ C, Ryan EM, Sacarlal J, Sogoloff B, Sorgho H, Tanner M, Theander T, Valea I, Volkman SK, Yu Q, Lapierre D, Birren BW, Gilbert PB, Wirth DF. Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine. N Engl J Med. 2015 Nov 19;373(21):2025-2037. doi: 10.1056/NEJMoa1505819. Epub 2015 Oct 21.
- Individual participant dataSharing planned: Yes. Data will be made available through the LSHTM Data Compass system
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alassane Dicko, Professor study director
Malaria Research & Training Center, Bamako
Jean Bosco Ouedraogo, Professor study director
Institut de Recherche en Sciences de la Santé, Direction Régionale de l'Ouest (IRSS-DRO)
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing RABIPUR®, RTS,S/AS01 and SMC with SP+AQ in people with Malaria,Falciparum and Children, Only, run by London School of Hygiene and Tropical Medicine at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Burkina Faso, Mali. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Clinical Episodes of Malaria (time frame: Passive surveillance of clinical episodes of malaria within the study area starting from the date of the first dose of study vaccines (April/May 2017) until 31st March 2020- a total of 36 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03143218, which also lists 24 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Apr 2022.