1. Post-discharge chemoprevention of malaria in transfused children; a randomized trial in Uganda & Kenya R Idro, R Opoka, A Dhabangi, F TerKuile, and K Phiri on behalf of the study team

2. Background 1.SA is a leading cause of hospital admissions and mortality in Africa. 2.Children <5 yrs are at high risk of readmission or death within 6 months after discharge. 3.This risk is particularly high in the first 3 months post-discharge. CountryPost discharge mortality Post discharge re- admissions within 6 months Author Malawi12.6%8%Phiri K et al 2008 KenyaCombined re-admissions or death – 17.9% Desai et al, unpublished UgandaCombined re-admissions or death – 36.5% Opoka et al, unpublished

3. Change in Haemoglobin Namazzi et al 2015 Mean pre and post transfusion Hb was 3.7 (SD 0.8)and 6.3 (SD 1.5) g/dL respectively. Mean volume of “red blood cells” transfused was 12.1 (S.D 4.1) mL/kg 24 hours after blood transfusion  Mean change 24 hrs and 6 wks after blood transfusion was 2.6 (SD 1.5) g/dL and 7.2 (SD 2.4) g/dL  Unit increase in haemoglobin per 10ml/kg of blood was 1.5g/dL  47/188(25%) required a second transfusion within 24 hours At 6 Weeks: mean change was 7.3g/dL (SD 1.6) 29/08/2015 UMA Conference,Mbale

4. Background and problem statement Malaria is a major contributor to the slow recovery of Hb, rebound severe anaemia and morbidity. – Haematological recovery from malaria-associated anaemia is known to take at least 6 weeks. – This period may be prolonged in those with persistent or new malaria infections due to on- going red cell destruction and red blood cell production failure.

5. Preliminary study In Malawi, 3 months three-day treatment courses of AL in children with SMA prevented 31% of deaths and readmissions. Phiri K et al Lancet Infect Dis. 2012;12(3):191-200.. – This effect was in addition to the effect of insecticide- treated bed nets. – These findings need to be confirmed in other settings before the WHO can consider PMC as a post-discharge management standard for severe anaemia.

6. Objectives Primary objective –Determine if 3 months of PMC with monthly 3-day treatment courses of DHA-P is safe and superior to the standard single 3-day treatment with AL in reducing all-cause re-admissions and deaths by six months in the post-discharge management of children <5 yrs with SA. Secondary objective –To determine the cost-effectiveness of post- discharge malaria chemoprevention of malaria with DHA-P compared to current standard of care.

7. Design 2,212 transfused children (1106 in Uganda and 1106 in Kenya) Randomised after 2 weeks Monthly (3 day courses) of DHA-P Placebo

8. Participants Inclusion criteria – Convalescent children aged 5 kg; – Admitted with and transfused for severe anaemia (Hb<5g/dL/ Ht<15%) – Clinically stable, able to take or switch to oral medication – Post-transfusion Hb >5g/dL. Exclusion criteria – Anaemia due to blood loss from trauma, malignancy, known bleeding disorder or sickle cell disease – Known hypersensitivity to the study drug – Known heart conditions – Known need at enrolment for prohibited medication – Scheduled surgery during the 6-month course of the study

9. Sample size – A sample size of 1106 children per arm (2212 total children) allows detection of a 30% reduction in deaths and all-cause readmission between wks 2-26 after enrolment from 17.6 to 12.3% with 10% loss to follow-up (power 90%, α=0.05).

11. Outcome measures Primary outcome – A composite of death and all-cause re-admissions between 2-26 weeks after enrolment. Secondary outcome measures are: – All-cause mortality – All-cause hospital re-admissions – Re-admissions due to SA or SM (requiring parenteral quinine or artesunate), – Non-severe all-cause sick-child clinic visits – Clinic visits because of RDT or microscopy confirmed non-severe malaria.

12. Data analysis Analysis by intention to treat – All events to capture the potential effect of PMC on reducing first and repeat events. – The protective efficacy (95% CI) will be calculated as 100 x (1–HR) – Incidence rates per child-year and absolute rate reductions.

13. Utility The study will provide Governments and the WHO with concrete data on which to base decisions on whether to introduce PMC as standard of care practice for children treated for SA in malaria endemic areas.

14. Collaborating institutions University of Bergen, Norway Liverpool School of Hygiene and Tropical Medicine, UK University of Amsterdam, The Netherlands Imperial College, London, UK Makerere University, Uganda University of Minnesota (to become Indiana University) University of Malawi, Malawi Kenya Medical Research Institute, Kenya Centers of Disease Control (Kenya) University of Massachusetts, USA University of North Carolina, USA Global Malaria Programme, WHO, Switzerland