Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202312551082722 Date of Registration: 06/12/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Severe Malaria A Research and Trials consortium - Multisite Adaptive Platform trial
Official scientific title Severe Malaria A Research and Trials consortium - Multisite Adaptive Platform trial SMAART-MAP trial
Brief summary describing the background and objectives of the trial Severe malaria remains a common cause of child hospitalisations and deaths in African children. Even on the best anti-malarial treatments (injectable artesunate) many African children with severe malaria have poor outcomes with most deaths occurring within within 24 hours of arrival to hospital. Children with the complications of altered consciousness and seizures (cerebral malaria), impaired renal function, or anaemia have poor outcomes. We have identified supportive (adjunctive therapies) for each of the complications and would like to test these in a multicentre Phase II trial using a platform trial design (master protocol with multiple domains). The objective of the trial is to identify promising adjunctive therapies to take forward into a large Phase III trial in severe malaria. The adaptive platform design enables additional domains to be added so a range of adjunctive therapies can be tested, across multiple clinical presentations of severe malaria, in a timely manner. The target population for the trial is children, aged >3 months and <12 years who are hospitalised with severe malaria in 7 sites in 6 countries (Uganda, Zambia, Ghana, Kenya, Democratic Republic of the Congo and Mozambique). Each domain will enrol 150 children randomising them 1:1 to a experimental intervention versus standard of care. Primary outcomes measured during admission will be specific to each domain. Secondary outcomes for all domains will include readmissions and mortality to day 28 and day 90; grade 3 or 4 adverse events (AEs) and AEs judged related to domain-specific interventions.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) SMAARTMAP
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Malaria
Purpose of the trial Supportive care
Anticipated trial start date 01/03/2024
Actual trial start date
Anticipated date of last follow up 30/10/2026
Actual Last follow-up date
Anticipated target sample size (number of participants) 450
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Central randomisation by phone/fax Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group No seizure prophylaxis none Up to 48 hours Standard of care with no parenteral levetiracetam as prophylaxis to prevent further seizures 75 Active-Treatment of Control Group
Control Group Standard dose paracetamol 10mg/kg no more frequently than every 8 hours for fever control For 66 hours (last dose) Standard recommended care for fever control in severe malaria 75 Active-Treatment of Control Group
Control Group Red Cell concentrate blood transfusion 10mls/kg if temperature is >37.5⁰C; 15mls/kg if temperature is ≤37.5⁰C During hospital admission (72 hours) Treatment of severe anaemia with standard red cell concentrate blood transfusion 75 Active-Treatment of Control Group
Experimental Group Parenteral levetiracetam 40 mg/kg loading dose and then 30mg/kg at 12 hours and 24 hours for all children, with doses at 36 hours and 48 hours only if the child has a temperature of >37.5°C or had a temperature of >37.5°C within the preceding 12 hours, or has a Blantyre Coma Score of ≤4. Dosing up to 36 hours or 48 hours only if the child has a temperature of >37.5°C or had a temperature of >37.5°C within the preceding 12 hours, or has a Blantyre Coma Score of ≤4 Seizure Prophylaxis-active arm 75
Experimental Group High dose paracetamol 20mg/kg every 6 hours given rectally, orally or via a nasogastric tube 66 hours Renal Protection-active arm 75
Experimental Group Whole blood Transfusion 20mls/kg if temperature at screening is >37.5⁰C or 30mls/kg if temperature is ≤37.5⁰C. Any second transfusion will follow the same dose During admission Blood transfusion with whole blood for severe anaemia 75
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Admitted to the paediatric ward in the last 24 hours Current or recent evidence of malaria (slide or rapid diagnostic test (RDT) positive in this admission) Guardian willing to provide consent Domain Specific criteria Cerebral Malaria Domain EITHER One or more reported seizures in the current episode of illness and altered consciousness (BCS≤4) at screening OR Presence of coma (BCS ≤2) at screening regardless of history Renal domain Creatinine >1.5xULN on point-of-care assay at screening Meet one of the current WHO severity criteria (clinical or laboratory (where these tests are done routinely)) (Group 1 and 2 from the recent WHO reclassification of severe malaria) Anaemia Domain Hb <6g/dl One or more or the following severity signs: Hb<4g/dl, prostration, impaired consciousness, respiratory distress, history of passing red or coca-coloured urine in this illness Domain Specific criteria Cerebral Malaria Domain Received an anticonvulsant within 6 hours of screening or between screening and randomisation. Known cerebral palsy or significant neuro-development delay. Renal Domain Received paracetamol within 6 hours of screening or between screening and randomisation Known allergy to paracetamol Severe malnutrition (middle upper arm circumference MUAC<11.5cm) Anaemia Domain Known congenital or valvular heart disease (not surgically corrected) Child: 6 Year-12 Year,Infant: 13 Month(s)-24 Month(s),Preschool Child: 2 Year-5 Year 6 Month(s) 11 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 10/11/2023 Imperial College Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Joint Research Compliance Office, Imperial College London Room 215, Level 2, Medical School Building Norfolk Place London W2 1PG United Kingdom
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 01/01/2024 SERU The National Ethics Approval committee
Ethics Committee Address
Street address City Postal code Country
PO Box 5440 00200 Nairobi 54400020 Kenya
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 15/01/2024 National Health Research Ethics Board
Ethics Committee Address
Street address City Postal code Country
Chalala Office Lot No 18961/M, Off Kasama Road Lusaka POB3007 Zambia
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 17/12/2023 Infectious Diseases Institute Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
IDI-McKinnell Knowledge Centre, College of Health Sciences, Makerere University, Kampala Kampala POB22418 Uganda
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 16/12/2023 Committee on Human Research Publication and Ethics
Ethics Committee Address
Street address City Postal code Country
Room7 Block J, School of Medical Sciences, Kwame Nkrumah University of Science and Technology Kumasi Uni PO Ghana
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 18/12/2023 CISM Internal Bioethics Committee for Health
Ethics Committee Address
Street address City Postal code Country
Twelfth Street Manhica CP 1929 Mozambique
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 07/01/2024 Ethics Research Committee University of Kinshasa
Ethics Committee Address
Street address City Postal code Country
University Avenue Kinshasa BP11850 Democratic Republic of the Congo
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Cerebral Malaria domain Number of witnessed seizures sufficient to start or change anticonvulsant medication 72 hours
Primary Outcome Renal Domain Area Under the Curve (AUC) for creatinine from randomisation 72 hours
Primary Outcome Anaemia domain change in haemoglobin adjusted for baseline 24 hours
Secondary Outcome Day 28 and Day 90 readmissions and mortality Day 28 and Day 90
Secondary Outcome Cerebral malaria domain outcomes • Time to fully regain consciousness (BCS 5 (the maximum score)) • Adverse events (AEs) of any grade judged related to anticonvulsants • Solicited AEs • Neurological sequalae During admission and Neurological sequalae Day 28 and Day 90
Secondary Outcome Renal domain outcomes: Creatinine at 24 hours (change from baseline, adjusted for baseline) Creatinine at 48 hours (change from baseline, adjusted for baseline) Creatinine at 72 hours (change from baseline, adjusted for baseline) Renal domain safety outcomes: Change in ALT and AST (liver enzymes) at 72 hours (adjusted for baseline) Adverse events (AEs) of any grade judged related to paracetamol AEs of any grade causing a change in paracetamol administration 24, 48 and 72 hours
Secondary Outcome Severe anaemia domain outcomes: Change in haemoglobin at 72 hours Number of additional transfusions in the acute admission Development of new profound anaemia (Hb<4g/dl) during acute admission or development of severe anaemia (Hb<6g/dl) post discharge Adverse Events (AEs) judged related to blood transfusion 72 hours or during admission
Secondary Outcome Grade 3 or 4 Adverse Events During admission
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Kilifi County Hospital Hospital Road Kilifi PO Box 23 Kenya
Mbale Regional Referral Hospital Pallisa Road Zone Mbale PO Box 91 Uganda
Soroti Regional Hospital Mbale-Soroti Road Soroti POBox 289 Uganda
Kalongo Hospital Pamol Road Kalongo 00000 Uganda
Manhica Health Research Centre Bairro Cambeve, Rua 12 Manhica POBOX1929 Mozambique
Komfo Anokye Teaching Hospital Ring Road Kumasi 000000 Ghana
FUNDING SOURCES
Name of source Street address City Postal code Country
Wellcome Trust 183 Euston Rd London NW1 2BE United Kingdom
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Imperial College Joint Research Office Commonwealth Building Du Cane Road, Hammersmith Campus London W12 0NN United Kingdom University
COLLABORATORS
Name Street address City Postal code Country
Mainga Hamaluba Kilifi County Hospital, Hospital Road Kilifi POBox230 Kenya
Elizabeth George MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, 90, High Holborn, 2nd Floor London WC1V 6LJ United Kingdom
A Sarah Walker MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, 90, High Holborn, 2nd Floor London WC1V 6LJ United Kingdom
Nick Day Mahidol Oxford Tropical Medicine Research Unit, 420/6 Rajvithi Road, Tungphyathai Bangkok 10400 Thailand
Arjen Dondorp Mahidol Oxford Tropical Medicine Research Unit, 420/6 Rajvithi Road, Tungphyathai Bangkok 10400 Thailand
Peter Olupot Olupot Mbale Regional Referral Hospital, Pallisa Road Zone Mbale POBox921 Uganda
Quique Bassat Hospital Central de Quelimane, Av.Julius Nyerere, Estrada regional numero 470, Bairro Namuinho, Manhica Health Research Centre Manhica POBox1929 Mozambique
Pedro Aide Hospital Central de Quelimane, Av.Julius Nyerere, Estrada regional numero 470, Bairro Namuinho, Manhica Health Research Centre Manhica POBox1929 Mozambique
Daniel Ansong Komfo Anokye Teaching Hospital, Bantama High Street Kumasi POBox1934 Ghana
Mike Chaponda St Pauls Mission Hospital Nchelenge POBox000 Zambia
Marie Onyamboko Kinshasa School of Public Health, Kin I School of Medicine Universite de Kinshasa, Campus UNIKIN, Lemba Kinshasa BP11850 Democratic Republic of the Congo
Maurice Akoa Dr. Ambrosoli Hospital, Hospital Road Kalongo POBox47 Uganda
Florence Aloroker Soroti Regional Referral Hospital, Hospital Road Soroti POBox289 Uganda
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Kathryn Maitland k.maitland@imperial.ac.uk +254710508749 Hospital Road
City Postal code Country Position/Affiliation
Kilifi POBox230 Kenya Professor of Paediatrics
Role Name Email Phone Street address
Public Enquiries Emmanuel Oguda EOguda@kemri-wellcome.org +254726957045 Hospital Road
City Postal code Country Position/Affiliation
Kilifi POBox230 Kenya Trial Manager
Role Name Email Phone Street address
Scientific Enquiries Kathryn Maitland k.maitland@imperial.ac.uk +254417522063 Hospital Road
City Postal code Country Position/Affiliation
Kilifi POBox230 Kenya Principal Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes We have a data sharing plan for investigator and external requests. Data from SMAART-MAP trial will be shared according to a controlled access approach (outlined above) in accordance to Wellcome (the funders) policy based on the following principles:  No data should be released that would compromise an ongoing trial or study.  There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose.  Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers.  The resources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources.  Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries. Informed Consent Form,Statistical Analysis Plan,Study Protocol IPD will be shared following a period of exclusivity as outlined above. The minimum period of exclusivity will be 2 years following the publication of the trial results. The study protocol, statistical analysis plan and ICF will be published after all ethics and regulatory approvals in an open access journal. Standard data request form should be completed and access granted by Trial Steering Committee (custodians of the trial data) where the resources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information