Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364: DOI: /NEJMoa

2 FEAST Fluid Expansion As Supportive Therapy in critically ill African children Full study title: A randomised trial of fluid resuscitation strategies in African children with severe febrile illness and clinical evidence of impaired perfusion Protocol version 1.2 Jan 26 th, 2009 MAIN SPONSOR: Imperial College London FUNDERS: Medical Research Council STUDY COORDINATION CENTRE: KEMRI Wellcome Trust Research Programme Kilifi, Kenya ISRCTN ICREC_8_1_1 Protocol authorised by: Name: Professor Elizabeth Molyneux Role: Chair of Trial Steering Committee Date: Signature: FEAST Page 1 26 th Jan 2009 version 1.2

3 Study Management Group Chief investigator Dr Kathryn Maitland, KEMRI Wellcome Trust Unit, P.O Box , Kilifi, Kenya Tel ; Fax (alternative Principal co-investigators* and investigators * Principal co-investigators (one per site) are indicated in bold Professor Mike Levin, Imperial College London (St Mary s Campus), Norfolk Place, London W2 1PG, UK. m.levin@imperial.ac.uk; Tel: + 44 (0) ; Fax: +44 (0) Professor Diana Gibb MRC Clinical Trials Unit, 222, Euston Road, London NW1 2DA, UK. dmg@ctu.mrc.ac.uk; Tel: ; Fax: Dr Jane Crawley MRC Clinical Trials Unit, 222, Euston Road, London NW1 2DA, UK. jmc@ctu.mrc.ac.uk; Tel: ; Fax: Dr James Tibenderana, Malaria Consortium Africa Regional Office, Kampala, Uganda j.tibenderana@malariaconsortium.org Tel: Fax: Kenya Dr Samuel Akech, KEMRI-Wellcome Trust Programme, P.O Box , Kilifi, Kenya sakech@kilifi.kemri-wellcome.org; Tel ; fax Professor Charles Newton, KEMRI-Wellcome Trust Programme, P.O Box , Kilifi, Kenya. cnewton@kilifi.kemri-wellcome.org; Tel ; fax Tanzania Dr George Mtove, Joint Malaria Programme, Teule hospital, P.O Box 81, Muheza, Tanzania. gmtove@nimr.or.tz ; Tel / ; Fax Dr Hugh Reyburn, Joint Malaria Programme, P.O Box 2228, KCMC, Moshi, Tanzania hugh.reyburn@lshtm.ac.uk ; Tel ; Fax FEAST Page 2 26 th Jan 2009 version 1.2

4 Professor Chris Whitty, Joint Malaria Programme, LSHTM, Keppel St, London WCI1E 7HT, UK. Tel ; Fax Uganda Mulago Hospital, Kampala Dr Sarah Kiguli, Department of Paediatrics, PO Box 7072 Makerere University, Kampala, Uganda. ; Tel ; Fax Dr Robert Opoka, Consultant Paediatrician Tel ; Fax Dr Justus Byarugaba Senior Paediatrician Tel ; Fax Soroti Dr Charles Engoru, Soroti Regional Hospital, P.O Box 289 Soroti. Tel ; Fax Lacor, Gulu Dr Richard Nyeko, St Mary s Hospital, Lacor PO 180 Gulu Richard_nyeko@yahoo.com; Tel ; Fax Mbale Dr Peter Olupot 0lupot, Mbale Regional Referral Hospital, P.O Box 921, Mbale. polupotolupot@yahoo.com; Tel ; Fax FEAST Study investigators Dr Hans- Joerg Lang: Trial Paediatric Coordinator Dr Trudie Lang: Head of Kilifi Clinical Trials Facility Dr Greg Fegan: Senior Statistician Nicolette Davies: Trial Administrator, Imperial College hajoe123@yahoo.es tlang@kilifi.kemri-wellcome.org gfegan@kilifi.kemri-wellcome.org nicolette.davies@imperial.ac.uk Trial statistician Professor Abdel Babiker, MRC CTU, Euston Road London agb@ctu.mrc.ac.uk; Tel ; Fax FEAST Page 3 26 th Jan 2009 version 1.2

5 Trial Management Group Kilifi Clinical Trials Facility KEMRI Wellcome Trust Research Programme, P.O Box , Kilifi, Kenya Tel ; Fax Mukami Mbogo: FEAST Trial Manager Gilbert Ogetii: FEAST Trial Monitor Moses Waweru FEAST Trial Monitor -Uganda Naomi Waithira FEAST Data Manager: Statistician: (TBA) Study Coordination Centre For general queries, supply of trial documentation, and collection of data, please contact: Study Coordinator: Mukami Mbogo Address: KEMRI Wellcome Trust Programme, P.O Box , Kilifi, Kenya Tel: Fax: Clinical Queries Clinical queries should be directed to Mukami Mbogo (Telephone: or (mobile number to be added) who will direct the query to the appropriate person Sponsor Imperial College (St Mary s Campus), Norfolk Place, London W2 1PG, UK Funder Medical Research Council, 20 Park Crescent, London W1B 1AL, UK FEAST Page 4 26 th Jan 2009 version 1.2

6 General information This protocol describes the FEAST Trial on the recruitment and management of trial participants. Every care was taken in its drafting, but corrections or amendments may be necessary. Any changes will be defined as modifications or amendments. Any such changes will be coordinated by the trial management team, taken through any ethics review or notification and then new versions issues to each centre by the trial management group. Problems relating to this trial should be referred, in the first instance, to the study coordination centre. This trial will adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) and the International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines. It will be conducted in compliance with the protocol, the Data Protection Act and other regulatory requirements as appropriate. FEAST Page 5 26 th Jan 2009 version 1.2

7 Table of Contents STUDY SUMMARY INTRODUCTION TRIAL OBJECTIVES Primary objectives Secondary objectives TRIAL OUTCOME MEASURES Primary endpoints Secondary endpoints TRIAL DESIGN STATISTICAL CONSIDERATIONS Randomisation Sample size calculation Analysis Plan PATIENT POPULATION ELIGIBILITY Inclusion criteria Exclusion criteria SCREENING AND INVESTIGATIONS RANDOMISATION AND ENROLMENT TREATMENTS Treatment Arms Post admission- all arms Non-trial treatment TRIAL PRODUCTS ASSESSMENTS AND FOLLOW-UP Follow up and loss to follow up Data for cost effectiveness analysis Quality of life questionnaire SAFETY REPORTING Definitions Causality Reporting Procedures TRIAL CLOSURE WITHDRAWAL OF PATIENTS TRIAL MONITORING CO-ENROLMENT ETHICAL CONSIDERATIONS TRIAL COMMITTEES PUBLICATIONS REFERENCES...38 APPENDICES...43 APPENDIX 1. CONSENT PROCEDURES...43 APPENDIX 2. PATIENT INFORMATION SHEET AND CONSENT...45 APPENDIX 3. CO-ENROLMENT WITH AQUAMAT...49 FEAST Page 6 26 th Jan 2009 version 1.2

8 GLOSSARY OF ABBREVIATIONS AE AR BP bpm CRF CRT CVP ERC HAS Hb HIV ICP IDMC ISRCTN KEMRI KCTF MOP MRC CTU PI PIS RCT RDT SAE Saline SAR SBP SMA SOP SSA SUSAR TMG TSC UAR U&E Adverse event Adverse reaction Blood pressure Beats per minute Case Report Form Capillary refilling time Central venous pressure Endpoint Review Committee 5% Human albumin solution Haemoglobin Human immunodeficiency virus Intracranial pressure Independent Data Monitoring Committee International standard randomised controlled trial number Kenya Medical Research Institute Kilifi Clinical Trials Facility Manual of operations Medical Research Council Clinical Trials Unit Principal Investigator Patient information Sheet Randomised controlled trial Rapid diagnostic test Serious adverse event 0.9% saline infusion Serious adverse reaction Systolic blood pressure Severe malarial anaemia Standard operating procedures Site specific assessment Suspected unexpected serious adverse reaction Trial Management Group Trial Steering Committee Unexpected adverse reaction Urea and electrolytes FEAST Page 7 26 th Jan 2009 version 1.2

9 GLOSSARY OF TERMS Coma Hypotensive shock Impaired perfusion Intravascular volume depletion Impaired consciousness Prostration Respiratory distress Inability to localize a painful stimulus Children with clinical signs of severe illness and impaired perfusion plus severe hypotension 1 of: capillary refill >2 seconds; lower limb temperature gradient; weak radial pulse volume; severe tachycardia Depletion of circulating volume : relative (due to vasodilatation) or actual (loss of fluid from intravascular space e.g. burns or blood loss or capillary leak) Prostration or coma Inability to sit unsupported, or to breast feed if <9 months Deep breathing or increased work of breathing Severe hypotension Systolic blood pressure <12 months: <50mmHg; 12 months to 5 years: <60mmHg; >5 years: <70mmHg Severe illness Children with impaired consciousness or respiratory distress Severe tachycardia Heart rate: <12 months: >180bpm; 12 months to 5 years: >160bpm; >5years: >140bpm KEYWORDS Children Infants Africa Kenya Tanzania Uganda Plasmodium falciparum malaria Sepsis Randomised controlled trial Human albumin solution Normal saline Fluid expansion Resuscitation Emergency medicine FEAST Page 8 26 th Jan 2009 version 1.2

10 STUDY SUMMARY TITLE: Fluid Expansion As Supportive Therapy in critically ill African children DESIGN A 3-arm randomised open comparative trial of fluid resuscitation strategies: (1) Immediate volume resuscitation with normal (0.9%) saline; (2) Immediate volume expansion with 5% human albumin solution (HAS); (3) Maintenance fluids, with no immediate volume expansion. AIMS In hospitals throughout sub-saharan Africa, mortality from malaria and other severe infections in childhood remains at 15-30%, with over 50% of deaths occurring within 24 hours of admission. Currently, antimalarial and antimicrobial drugs are the mainstay of treatment, with little consideration being given to the use of adjunctive supportive therapies. There is considerable debate about the degree to which intravascular volume depletion (hypovolaemia) contributes to the pathophysiology of malaria and other severe infections, and clinical practice varies widely across the continent. To resolve the continuing uncertainty, this multi-centre randomised clinical trial will evaluate different fluid resuscitation strategies in children presenting to hospital with severe febrile illness and clinical evidence of impaired perfusion, with the intention of generating data of practical value to clinicians working in resource-poor settings in Africa. OUTCOME MEASURES Primary Endpoint: In-hospital mortality at 48 hours after randomisation. Secondary Endpoints: Mortality at 4 weeks, neurological sequelae at 4 weeks and 24 weeks, episodes of hypotensive shock within 48 hours of randomisation, adverse events related to fluid resuscitation (pulmonary oedema, intracranial hypertension or severe allergic reaction to those receiving albumin). POPULATION Sample size The total sample size is 2,880 children. Assuming that the background 48-hour mortality rate in the trial population is 15% and that 67% of eligible children will have P. falciparum parasitaemia (an important sub-group for which the trial will be adequately powered), the planned sample size will provide at least 80% power to detect a difference of 30% in 48- hour mortality between the saline and control arms and a difference of 40% between the HAS and saline arms, with type I error probability α = 0.05 and allowing for multiple comparisons. FEAST Page 9 26 th Jan 2009 version 1.2

11 ELIGIBILITY Inclusion criteria Children aged >60 days and <12 years with severe febrile illness (impaired consciousness or respiratory distress) plus clinical evidence of impaired perfusion. Exclusion criteria Children with the following conditions will be excluded: severe acute malnutrition; gastroenteritis; chronic renal failure, pulmonary oedema and other conditions in which volume expansion is contraindicated; non-infectious causes of severe illness; children who have already received an isotonic volume expander during the current illness. TRIAL TREATMENT 2,880 eligible children will be randomly assigned in a ratio of 1:1:1 to one of three fluid management arms: (1) Rapid volume expansion with 20mls/kg intravenous 0.9% saline; (2) Rapid volume expansion with 20mls/kg 5% human albumin solution (HAS); (3) Maintenance fluids with no volume expansion (control arm). Children will be reassessed at 1, 4, 8, 24 and 48 hours, and further fluid boluses will be given in strict accordance with the protocol. Children will receive a maximum of 80mls/kg in 24 hours of fluid boluses. The small number of eligible children that are anticipated to have hypotensive shock (severe hypotension plus impaired perfusion) at the time of admission (n=144) will be randomly allocated in a ratio of 1:1 to rapid volume expansion with either saline or HAS. Follow-up Children will be clinically assessed at 1, 4, 8, 24 and 48 hours. Neurological assessments will be carried out at 4 weeks and, for those with sequelae at 4 weeks, at 24 weeks from the time of randomisation. Follow-up neurological assessments will be carried out by a clinician or nurse who is blind to treatment allocation. DURATION The trial will enrol over 24 months and will start in July FEAST Page th Jan 2009 version 1.2

12 Trial Schema Time Admission Eligible patient with: Severity criteria a plus a sign of impaired perfusion b FEAST A Intravascular volume depleted group No Systolic Blood pressure <50 <60, <70 mmhg for ages< 1y,1-4y,>=5y Yes FEAST B Hypotensive shock group 5% albumin (HAS) 20mls/kg over 1hr 0.9% saline 20mls/kg over 1hr Control No bolus 5% albumin (HAS) 40mls/kg over 1hr 0.9% saline 40mls/kg over 1hr One hour Three options, based on clinical signs at one hour : b 1/ Evidence of impaired perfusion B olus of interventio n fluid 20mls/kg*; or 2/ Hypotensive shock cd Bolus of interventio n fluid 40 mls/kg*; *Note: b oluses given over 1 hour* or 3/ No signs of impaired perfusion Maintenance fluids only >=2 hours Control (no bolus) Maintenance fluids only Only if hypotensive shock c has developed : Rescue with N/saline bolus 40mls/kg over one hour ALL CHILDREN Maintenance fluids only Three options, based on clinical signs at one hour: 1/ Evidence of impaired perfusion b Bolus of interventio n fluid 20mls/kg*; or 2/ Hypotensive shock cd Bolus of interventio n fluid 40 mls/kg*; *Note: boluses given over 1 hour* or 3/ No signs of impaired perfusion Maintenance fluids only The only indication for (additional) fluid boluses will be hypotensive shock c Hypotensive shock Interventio n groups: treat with allocated fluid 40mls/kg over 1 hour Control: Rescue with N/saline bolus 40mls/kg over 1 hour * d Maximum Bolus Volume = 80mls/kg per any 24 hour period* a Severity criteria: Impaired consciousness &/or respiratory distress b Impaired perfusion : One or more features of o capillary refill >2secs o temperature gradient o weak pulse volume o severe tachycardia :heart rate> 180, >160 and >140 bpm for ages < 1y, 1-4y,>=5y c Hypotensive shock Systolic BP <50<60, <70 mmhg for ages < 1y,1-4y,>=5y PLUS one or more features of impaired perfusion All children : correct hypoglycaemia, treat seizures if indicated, start oxygen if saturations < 95%, commence antimalarials & antibiotics d Maximum total bolus volumes: In the rare case where fluid volume has reached daily recommended maximum bolus volume, at the discretion of the clinician, a further fluid bolus of 20mls/kg may be given if they feel this may be life saving. FEAST Page th Jan 2009 version 1.2

13 Trial Flow Sheet Assessment Time Admission 1hr 4hr 8hr 24hr 48hr Discharge 28 days 6 months Procedure Clinical assessment Laboratory tests X X X X X X X X X X X X Stored blood X X X Neurological exam X X X CRF X X X X X X X X X Quality of Life X FEAST Page th Jan 2009 version 1.2

14 1. INTRODUCTION 1.1 BACKGROUND AND RATIONALE Malaria and other infectious diseases pose a major health burden for children in sub-saharan Africa (SSA), accounting for millions of deaths annually [1]. Little progress has been made towards reducing current mortality rates of 15-30% for children admitted to hospitals in SSA with lifethreatening infections[2-6]. Currently, anti-malarial and antimicrobial drugs are the mainstay of treatment for severe infections, and little consideration is given to the use of adjunctive supportive therapies [7-9]. Child survival programmes have largely ignored the role of triage and emergency care in reducing child mortality, despite the fact that these interventions may be highly cost-effective [4, 10]. Globally, the consensus view of paediatricians delivering care to critically sick children is that emergency clinical management should be standardised, and should target key aspects of deranged physiology, irrespective of the underlying disease process [11-14]. An important example is the management of paediatric septic shock, where the introduction of life support training programmes to ensure early recognition and rapid resuscitation has, in countries with neonatal and paediatric intensive care facilities, been associated with a marked improvement in outcome over the past 20 years [15-17]. The situation is markedly different in poorly-resourced hospitals in SSA, where sophisticated pointof-care tests, intensive care monitoring and specialist clinical care are rarely available. Over 50% of childhood deaths in African hospitals occur within 24 hours of admission, and hypotensive shock complicates many of these cases [8]. Adoption of simple treatment algorithms for the treatment of hypovolaemia and prevention of shock (irrespective of aetiology) could be of great benefit, but their effectiveness and safety have not been rigorously evaluated. Severe sepsis syndromes in childhood Children with life-threatening infections commonly present to hospital with complex pathophysiology. Whilst there is great variation in the host immune response to different pathogens, the convergence and rapid kinetics of subsequent immune pathways means that infection with a variety of different pathogens may result in a similar clinical picture [18, 19]. It is now accepted that sepsis syndrome, or severe inflammatory response syndrome (SIRS), can result from a range of viral, fungal, parasitic and non-infectious insults [20-22] and, once established, can progress relentlessly, regardless of the initial infection. This has resulted in a generic approach to care, which prioritizes immediate treatment of life-threatening complications, such as shock. Paediatric shock is associated with intravascular volume depletion (hypovolaemia), and death usually results from low cardiac output with high systemic vascular resistance rather than low systemic vascular resistance, as previously observed in adults [23, 24]. Consequently, children generally respond well to volume resuscitation, and international guidelines now recommend volume expansion as first-line treatment for all cases of severe paediatric shock and, less commonly, additional inotropic support for those with fluidrefractory shock (defined as requiring greater than 60mls/kg at admission to restore perfusion) [11, 12, 25, 26]. FEAST Page th Jan 2009 version 1.2

15 Clinical similarities between severe malaria and severe sepsis syndrome Severe falciparum malaria in African children has been well documented over the past decade [27-31], and is now known to include a complex range of physiological derangements, including severe anaemia, multi-organ dysfunction and biochemical abnormalities, features that are also characteristic of severe sepsis syndromes [21, 22, 32]. Co-existing bacteraemia occurs in up to 12% of children with clinical features of severe malaria [33-35], and simple bedside and laboratory assessment fails to distinguish between severe malaria and microbiologically-proven sepsis [35-39]. Brain swelling, shock and profound anaemia are life-threatening complications of malaria in children [40-42], whereas pulmonary oedema [43], renal and hepatic failure are recognised complications in adults [27]. Approximately 12% of children surviving cerebral malaria are left with neurological sequelae, and cognitive and behavioural problems are increasingly recognized [44-49]. For many years, cerebral malaria and congestive cardiac failure were thought to account for the majority of deaths from severe malaria in children, and fluid restriction was therefore recommended [50, 51]. Since >50% of deaths from severe malaria occur before maximal therapeutic benefit can be obtained from quinine [28, 29], use of adjunctive therapies could improve outcome. Respiratory distress, a common feature of severe malaria in children, and originally thought to be caused by congestive cardiac failure, is now recognised as an indicator of metabolic acidosis and hypovolaemia, and is predictive of poor outcome [52, 53]. Recent work from Kenya has established that hypovolaemia is a feature of severe malaria in children [54, 55], with low central venous pressure, severe tachycardia and delayed capillary refill time (CRT), clinical signs of impaired perfusion (hypovolaemia), being commonly observed at the time of admission. Up to 15% of patients were hypotensive, a feature of advanced hypotensive shock. In a trial from Ghana, delayed CRT, a simple test of impaired perfusion, was an independent predictor of mortality in severe malaria [56]. Studies from Gabon have documented moderate dehydration in children with severe malaria, and a clear correlation between dehydration and depth of coma [57]. What remains unresolved is whether rapid and early restoration of intravascular volume results in a superior outcome compared to slow corrections of deficits by low volume maintenance fluids. Until this is resolved the rapid correction of intravascular volume deficits to restore perfusion by intravenous fluid resuscitation in children with severe malaria remains controversial [58, 59]. Current fluid management strategies for critically ill African children Although there is evidence to suggest that hypovolaemia contributes to the pathophysiology of severe malaria, there are conflicting recommendations as to how it should be treated. Recently published WHO guidelines suggest that children may respond favourably to a fluid bolus because of concomitant dehydration, but specific recommendations regarding the type, rate or volume of fluid administration are not provided [59]. Use of invasive central venous pressure (CVP) monitoring is recommended to monitor fluid replacement [59], yet this is not available, nor feasible, in most African hospitals. Currently, the vast majority of children with severe malaria in SSA hospitals receive no specific fluid management apart from blood transfusion, which is recommended for the management of severe anaemia [60]. Intravenous 10% glucose 80mls/kg/day is given as maintenance fluid requirements in some centres [61], yet in the presence of fever this represents modest fluid restriction. In resource-limited settings, WHO currently recommends rapid intravenous administration of 20mls/kg Ringers Lactate solution or 0.9% saline only for the treatment of advanced hypotensive FEAST Page th Jan 2009 version 1.2

16 shock (defined as cold hands or feet, weak rapid pulse and capillary refill time >3 seconds) in children [7, 62]. Evaluation in 3837 Brazilian children attending the emergency department, using these criteria identified shock in only 4 children (0.1%), all of whom died [63]. The guidelines state that boluses of fluid may be repeated twice, to a maximum total volume of 60mls/kg. Extreme caution is advised and recommends that fluid restoration is withheld or stopped in the presence of an enlarged liver, gallop heart rhythm or signs indicating raised jugular venous pressure. The former two features are non-specific as they are common in malaria endemic areas and the later sign is highly insensitive. Although this approach is broadly recommended for all conditions except severe malnutrition, recent WHO guidelines for the management of severe malaria, gastroenteritis and severe malnutrition differ with respect to both clinical assessment and the type and volume of fluid recommended for resuscitation [7, 62]. Development of an evidence-based approach to fluid management of the critically sick child in resource-poor settings is urgently needed. Possible risks of volume expansion To support a generic approach to volume expansion in sick children, the benefits should substantially outweigh risks. The major risks of volume expansion are volume overload, manifest as pulmonary oedema, brain swelling or raised intracranial pressure, and acute allergic reactions to infusion fluids. Most hospitals in resource-poor settings lack the clinical personnel and basic equipment that are required for meticulous patient monitoring, and this represents a major barrier to the widespread endorsement of volume expansion. Data from Kenya suggest, however, that pulmonary or cerebral oedema rarely complicate volume expansion in children with severe malaria, while no adverse reactions were observed in 135 children who received HAS [54, 64-66]. Globally, serious adverse events and allergic reactions to HAS are extremely rare [67]. Whilst rapid and early restoration of volume depletion using fluid boluses of 20-40mls/kg may be regarded as safe in shocked, previously healthy, well-nourished children with ready access to intensive care facilities, this may not be true of children with poor nutritional status and/or anaemia, who are generally managed on general paediatric hospital wards in SSA, and who have no access to intensive care, where slow restoration may be more relevant. Particular concern has been raised in relation to children with septic shock complicating encephalopathy or meningitis, severely anaemic children, and those with severe malnutrition and HIV. Encephalopathy and meningitis Doubt had been raised over the safety of volume expansion in children with severe meningitis or encephalopathy complicated by septic shock. However, cerebral perfusion is dependent on adequate cardiac output, and recent studies have shown that, compared to intravascular volume expansion, modest fluid restriction was detrimental to brain perfusion and outcome in severe meningitis [68, 69]. International guidelines now advocate correction of fluid deficits in children with meningitis [12, 70]. Severe malarial anaemia Among children with severe malarial anaemia (SMA), highest mortality is observed in those with concomitant respiratory distress (symptomatic SMA) [31, 71, 72]. Case fatality rates of children with symptomatic SMA range from 20-30%, rising to >35% when associated with impaired consciousness [72, 73]. The majority of deaths occur in children whilst awaiting transfusion [53, 72, 74]. There is now evidence to suggest that the haemodynamic characteristics of symptomatic SMA FEAST Page th Jan 2009 version 1.2

17 are more characteristic of hypovolaemia than of cardiac failure [40, 54]. As a result, it has been reasoned that moderate volume expansion with an intravenous bolus of fluid might restore circulation, and thus stabilize the condition of children awaiting transfusion for symptomatic SMA. Preliminary evidence provided by a randomised controlled trial suggests that pre-transfusion management with an intravenous bolus of 0.9% saline 20mls/kg is safe, improves clinical and biochemical markers of hypovolaemia and improves outcome, compared to a control arm [64]. Severe malnutrition and HIV There have been few detailed studies examining the pathophysiology and outcome of severe bacterial or malaria infections in HIV-infected children in Africa [75-77]. Current WHO guidelines for the treatment of shock in children with severe malnutrition (severe wasting or kwashiorkor) differ markedly from recommendations for children with normal nutritional status, with extreme caution being expressed in relation to the use of isotonic volume expansion [7, 9, 78]. Although this approach is currently undergoing further evaluation, children with severe malnutrition will be excluded from the FEAST trial. Volume expansion with HAS risks and benefits An early meta-analysis suggested that HAS may cause harm when administered predominantly to adults with a wide range of underlying conditions [79]. This conclusion has not been endorsed by further meta-analyses [80, 81], and by the results of a large trial on adults (the SAFE trial), in which a non-significant trend towards superiority of HAS over saline was observed in the subgroup of adults with sepsis [82]. Based on data from 3 studies [54, 65, 66], it has been estimated that HAS, at a cost of approximately US$ 35 per treatment, would be cost-effective over 0.9% saline for a decision-maker prepared to pay US$ 8.83 per life gained (T. Ades-personal communication). Choice of fluid for intravascular volume expansion Several resuscitation fluids are available for the treatment of severe dehydration or shock in children. Simple electrolyte solutions are of proven benefit in most situations where excess water and electrolytes depletion has resulted from gastroenteritis or shock due to burns. In conditions where hypotensive shock results from a sepsis-like syndrome, the choices include isotonic crystalloids or colloids[83]. Isotonic crystalloids, such as Ringers Lactate and 0.9% (normal) saline, equilibrate freely across the intra- and extra-vascular compartments of the extracellular space, so are favoured for restoration of circulating volume. Human albumin solution (HAS) and the synthetic colloids (gelatins, dextrans and starches) are also isotonic solutions, but their oncotic pressure means that their effect is mainly confined to expansion of the intravascular compartment and thus may restore circulating volume [67, 84, 85]. Three recent trials in Kenya have compared different fluids in children with severe malaria and signs of hypovolaemia [54, 65, 66]. A meta-analysis of the combined data has also been undertaken (ref). Up to 40mls/kg of 0.9% saline or HAS was found to be safe and corrected haemodynamic indices of hypovolaemia[54]. In an open, randomised comparison of saline and HAS in 117 children with severe malaria and acidosis, mortality in children treated with HAS was 3.6% (2/56), compared to 18% (11/61) in those treated with saline (P=0.01) [65]. In the subgroup of children with coma, only 1/21 (5%) of children those who received HAS died, compared with 11/24 (46%) who received saline (P =0.002). A small but non-significant increase in neurological deficits was seen in the HAS arm (6/54) compared to the saline arm (2/50) [65]. In a further trial, mortality of children was lower in patients treated with HAS (1/44; 2.3%) than in those treated with the synthetic colloid Gelofusine (7/44; 16%) [66]. In the sub group in coma, 1/ 25 (4%) FEAST Page th Jan 2009 version 1.2

18 of HAS recipients died compared to 6/23 (26%) in the Gelofusine arm (P=0.04). Neurological sequelae complicated 3/43 (7%) survivors receiving HAS and 1/37 (3%) survivors receiving Gelofusine [66]. Of the nine, mainly small, randomised trials of volume expansion that have been conducted in children, three have been undertaken in dengue shock syndrome (DSS) [86-88], four in severe malaria [54, 64-66], one in severe dehydration [89] and one sepsis [90]. Most have failed to identify clear benefits of resuscitation with HAS or colloids over crystalloids. The largest randomised trial was undertaken in Vietnamese children with dengue shock syndrome, and showed no difference between Ringers Lactate and the artificial colloids, Dextran 40 and Hetastarch [88]. These results may not be relevant to severe malaria or sepsis, however, as dengue shock, caused by intense capillary leak, develops slowly over days resulting in haemoconcentration, whereas shock in severe malaria progresses rapidly and is associated with early mortality [91]. In addition, children with cerebral malaria have the attendant risk of brain swelling, where colloids due to their oncotic effects may show benefit, whereas neurological complications in DSS are rare [92]. In some parts of SSA, 19-50% of all paediatric admissions receive a blood transfusion [72, 93]. In many hospitals, transfusion services are poorly developed and cannot provide adequate supplies of blood for emergency transfusion depletion [94, 95]. Two studies have demonstrated that over 60% of the deaths from severe malaria anaemia occur in children awaiting blood transfusion, the speed of clinical response being critical to survival [53, 74, 96]. Although blood could be used for volume expansion, WHO guidelines suggest that in children with Hb>5g/dl the benefit is questionable [27, 97, 98]. Any short term benefit needs to be balanced by the risk of exposure to unsafe blood. In areas where the seroprevalence of HIV, hepatitis B and C and syphilis is high, 57% of donated blood remains unscreened for infection [99-101]. Blood transfusions continue to be a major source of preventable HIV infection in SSA, accounting for 10-15% of new HIV infections in children [100, 102, 103]. The cost of transfusion is substantial, estimated at between US$30 and US$50 in most localities across Africa, a cost that is often recouped from families [101, 104, 105]. Summary There is an urgent need for robust evidence to guide the fluid management of children with malaria and other severe febrile illnesses in resource-poor settings. Early recognition and prompt, appropriate treatment of children with signs of intravascular volume deficit (hypovolaemia) may prevent the development of advanced decompensated shock associated with hypotension, and reduce the current, unacceptably high mortality of children admitted to hospitals in sub-saharan Africa. FEAST Page th Jan 2009 version 1.2

19 2. TRIAL OBJECTIVES The FEAST trial addresses the question of whether fluid resuscitation to rapidly restore intravascular volume depletion in African children with severe febrile illness and clinical evidence of impaired perfusion is safe and results in improved survival compared to standard case management. More specifically, the trial has been designed with the aim of resolving the current debate over: a) Whether rapid correction of intravascular volume, using colloidal or electrolyte solutions, is safe and improves both survival and neurological outcome in children with severe falciparum malaria; and b) Whether this approach is preferable to slow restoration of total body water deficits, as suggested by other clinical researchers and currently recommended in international guidelines [58, 106]. 2.1 Primary objectives a) To establish whether rapid and early intravascular volume expansion with saline results in a lower mortality than standard slow replacement (maintenance fluids only) in children with severe febrile illness (impaired consciousness and/or respiratory distress) and clinical evidence of impaired perfusion. b) To establish whether rapid and early intravascular volume expansion with albumin is superior to saline in reducing mortality of children with severe febrile illness (impaired consciousness and/or respiratory distress) and clinical evidence of impaired perfusion. 2.2 Secondary objectives a) To establish whether intravascular volume expansion with saline results in improved survival without neurological deficit compared to standard management (maintenance fluids only) in children with severe falciparum malaria and clinical evidence of impaired perfusion. b) To establish whether intravascular volume expansion with albumin is superior to saline in improving survival without neurological deficit in children with severe falciparum malaria and clinical evidence of impaired perfusion. c) To assess whether the survival benefits of volume expansion with albumin or saline, if established, are evident in all children or are confined to the subgroup of children with coma. d) To assess the safety of volume expansion in relation to pulmonary oedema, raised intracranial pressure and allergic reactions to the infusion fluids (particularly HAS). e) To estimate the cost-effectiveness and budget impact of intravascular volume expansion with albumin or saline compared to maintenance fluids in the management of children with severe falciparum malaria and clinical evidence of impaired perfusion. FEAST Page th Jan 2009 version 1.2

20 3. TRIAL OUTCOME MEASURES 3.1 Primary endpoints a) Mortality at 48 hours after randomisation 3.2 Secondary endpoints a) Mortality at 4 weeks after randomisation b) Mortality or neurological sequelae at 4 weeks after randomisation c) Neurological sequelae at 4 weeks after randomisation d) Persistent neurological sequelae at 6 months after randomisation e) Development of hypotensive shock within 48 hours of randomisation f) Adverse event within 48 hours of randomisation (pulmonary oedema; intracranial hypertension; severe allergic reaction in those receiving albumin) 4. TRIAL DESIGN FEAST is a three-arm open randomised controlled comparison of fluid resuscitation strategies in 2,880 African children with severe febrile illness and clinical evidence of impaired perfusion. The trial will be conducted at sites in Kenya, Tanzania and Uganda. Eligible children will be divided into 2 groups on the basis of admission blood pressure: FEAST A (intravascular volume depletion): All eligible children except those with hypotensive shock at the time of admission will be randomly assigned to one of three fluid management arms in a ratio of 1:1:1: a) Saline: rapid volume expansion with 20mls/kg 0.9% saline given by intravenous infusion over one hour. Children will be reassessed at one hour, and a further bolus of saline will be given to those with persisting signs of impaired perfusion. b) Albumin: rapid volume expansion with 20mls/kg 5% human albumin solution (HAS) given by intravenous infusion over one hour. Children will be reassessed at one hour, and a further bolus of saline will be given to those with persisting signs of impaired perfusion. c) Control: low volume maintenance fluids in accordance with national guidelines, with no immediate volume expansion. FEAST B (hypotensive shock): Eligible children with hypotension shock (severe hypotension* plus signs of impaired perfusion) at the time of admission will not enter the control arm of the trial, but will be randomly assigned to receive volume expansion with either saline or HAS in a ratio of 1:1. * Severe hypotension: children <12 months: systolic blood pressure (BP) <50mmHg; 12 months to 5 years: systolic BP <60mmHg; >5 years: systolic BP <70mmHg. FEAST Page th Jan 2009 version 1.2

21 a) Saline: Intravenous infusion of 0.9% saline 40mls/kg over one hour #. Children will be reassessed at one hour, and a further bolus of saline will be given to those with persisting signs of impaired perfusion. b) Albumin: Intravenous infusion of 5% human albumin solution (HAS) 40mls/kg over one hour #. Children will be reassessed at one hour, and a further bolus of HAS will be given to those with persisting signs of impaired perfusion. # Saline or HAS 40mls/kg over one hour will be given to this critically ill group of children with an increased risk of mortality. 5. STATISTICAL CONSIDERATIONS 5.1 Randomisation Randomisation will be stratified by clinical site. Permuted blocks with randomly varying block size will be used to ensure balance in the number of children allocated to each treatment arm. Eligible trial participants, without hypotensive shock on admission, will be randomly allocated in a 1:1:1 ratio to one of the three treatment arms: immediate volume expansion with 5% human albumin solution (HAS), immediate volume expansion with 0.9% saline or no immediate fluid bolus (control). Eligible children with hypotensive shock (FEAST B) on admission will be allocated in a 1:1 ratio to immediate volume expansion with either HAS or saline. The randomisation schedule will be prepared by the CTU and implemented at the clinical sites using sealed envelopes. 5.2 Sample size calculation The sample size calculation is based on the primary endpoint (mortality at 48 hours) using two main comparisons saline versus control in children without hypotensive shock (FEAST A: Intravascular volume depletion) at entry and HAS versus saline in all eligible children children will be enrolled in the trial. Children with P. falciparum parasitaemia constitute an important sub-group for which the trial will be adequately powered. Assumptions: Baseline mortality of eligible children is 15% 67% of those with inclusion criteria will have P.falciparum parasitaemia 5% of children enrolled in the trial present with hypotensive shock on admission Background 48-hour death rate is 33% in children presenting with hypotensive shock Bolus 0.9% saline reduces mortality by 30% compared to maintenance fluids Bolus HAS reduces mortality by 40% compared to 0.9% saline Power 80% and α = 0.05, adjusted for two primary comparisons (saline versus maintenance fluids and HAS versus saline). With these assumptions, the table below shows that a total of 2880 children would provide sufficient power to detect a significant difference in 48-hour mortality between a) Saline and no bolus and b) FEAST Page th Jan 2009 version 1.2

22 HAS and saline, both overall and when restricted to children with P. falciparum parasitaemia at entry. 144 (5%) of these children would be expected to present with hypotensive shock, and will only contribute to the comparison between HAS and saline. Proportn 48H death rate HShock Eligible Total Power: Saline vs control Power: HAS vs Saline PF + HShock Eligible Overall n n N Overall PF+ Overall PF LEGEND: Propn PF+: proportion of children with P.falciparum parasitaemia; Eligible: children fulfilling entry criteria but without hypotensive shock; HShock: hypotensive shock; Co-enrolment to the AQUAMAT study, a randomised trial comparing quinine and artesunate for the treatment of severe malaria (see Appendix 3.0), will occur at the Kilifi and Tanzania study sites only. It is anticipated that, over the 2-year duration of the FEAST study, approximately 400 children admitted to these sites will have P. falciparum parasitaemia, and will therefore be eligible for coenrolment to both FEAST and AQUAMAT. Assuming that the mortality of the 200 children in the AQUAMAT study who are allocated to artesunate is 25% lower than those allocated to quinine, this will have a minimal impact on the assumed mortality of 15% for the 1,870 children with P. falciparum parasitaemia (67% of total study population of 2,880) who are recruited to FEAST (see Appendix 3 for summary and justification). 5.3 Analysis Plan The primary analysis will compare a) saline versus no bolus control and b) HAS versus saline in terms of the proportion of children with fatal outcome 48 hours after randomisation using a chisquare test adjusted by stratification for malaria parasitaemia and for the presence of coma at baseline. Secondary analysis will include the following comparisons: FEAST Page th Jan 2009 version 1.2

23 - saline versus control in terms of survival without neurological deficit - HAS versus saline in terms of survival without neurological deficit - combined arms saline/has versus control in terms of both survival and survival without neurological deficit - HAS versus control in terms of both survival and survival without neurological deficit Children with malaria parasitaemia and those with coma at entry constitute important subgroups. Pairwise comparisons between the allocated fluid management strategies in terms of the primary and secondary outcomes will be undertaken within these subgroups. Interim reviews \At least 3 interim reviews (after 300, 600 and 900 patients have been enrolled) will be held during the trial. These will review data on enrolment, safety, adherence to randomised strategies, efficacy and safety at regular intervals and in strict confidence. A decision to discontinue recruitment, in all patients or in selected subgroups, will be made only if the results are likely to convince the general clinical community and participants in the trial. The IDMC will report to the Trial Steering Committee (TSC) and to the Ethics Committee in each country, if, in their view, the data provide proof beyond reasonable doubt that one of the allocated strategies is better than its comparator in terms of the primary outcome. The guiding statistical criterion for proof beyond reasonable doubt is the Haybittle-Peto criterion of a difference of at least 3 standard deviations in an interim analysis of a major endpoint. The TSC will then decide whether to amend (including the possibility of dropping one of the three fluid intervention strategies) or stop the trial before the end of the planned follow-up. If a decision is made to continue, the IDMC will advise on the frequency of future reviews of the data on the basis of accrual and event rates. The IDMC will make recommendations to the FEAST Trial Steering Committee as to the continuation of the trial. 6. PATIENT POPULATION Children aged >60 days and <12 years admitted to the paediatric ward with a history of fever and/or an abnormal temperature: pyrexia ( 37.5 o C) or hypothermia (<36 o C). Parents or guardians must be willing and able to follow the consent procedure described below. 7. ELIGIBILITY 7.1 Inclusion criteria Children with severe illness AND clinical evidence of impaired perfusion in whom there uncertainty as to the benefits of immediate fluid resuscitation and what type of fluid to give. Severe illness and impaired perfusion are defined as follows: 1. Severe illness: one or more of the following: Impaired consciousness: prostration or coma Respiratory distress FEAST Page th Jan 2009 version 1.2

24 Prostration: inability to sit unsupported, or to breast feed if < 9months Coma: inability to localise a painful stimulus Respiratory distress: Deep breathing or increased work of breathing 2. Impaired perfusion: one or more of the following: Capillary refill > 2s Lower limb temperature gradient Weak radial pulse volume Severe tachycardia Severe tachycardia: <12 months: >180bpm; 12 months to 5 years: >160bpm; >5 years: >140 bpm 7.2 Exclusion criteria One or more of the following at admission: 1. Severe acute malnutrition 2. Gastroenteritis 3. Conditions where intravascular volume expansion is contraindicated, namely chronic renal failure, pulmonary oedema 4. Non-infectious causes of severe illness: trauma; burns; intoxication 5. Children who have already received volume expansion using an isotonic volume expander during the current illness Severe malnutrition: visible severe wasting and/or kwashiorkor Gastroenteritis: > 3 watery stools in previous 24 hours Pulmonary oedema: oxygen saturation <90% on pulse oximetry plus bilateral basal crepitations 8. SCREENING AND INVESTIGATIONS 8.1 Screening procedure Eligible children will be identified by the nurse and clinician on duty and registered in the eligibility screening log. A member of the trial team will then perform a rapid structured assessment of conscious level, heart rate, oxygen saturation (pulse oximetry), respiratory pattern, axillary temperature, blood pressure, capillary refill time and assessment of lower limb temperature. Details of those fulfilling the entry criteria will be entered onto a screening form, while reasons for noneligibility will be added to the eligibility screening log. Entry criteria will be based on clinical assessment alone. It is anticipated that this process will take approximately 5 minutes. 8.2 Laboratory investigations Venous blood will be taken on admission and prior to randomisation for the following investigations: Haemoglobin (Hb) Urea and electrolytes (U&E), acid-base status, lactate, glucose Malaria slide, malaria rapid diagnostic test (RDT) Blood culture, plasma, red and white cell pellet (for DNA extraction) stored for subsequent microbiological, virological diagnostic assays and genetic studies. FEAST Page th Jan 2009 version 1.2

25 In accordance with national guidelines, a plasma sample for HIV testing will be taken after admission procedures are complete and assent given by parents or guardians. Repeat samples for FBC, glucose, acid-base status and lactate will be taken at 8 hours and 24 hours. Blood will be taken from an indwelling intravenous cannula to avoid the need for repeat venepuncture. All blood volumes will be kept to a minimum. Any blood taken for research purposes under emergency deferred consent (see Appendix 1.0 for consent procedures) from children whose parents subsequently refuse consent will be discarded. 9. RANDOMISATION AND ENROLMENT 9.1 Consent Prospective written, informed consent will be sought from parents or guardians of children who are considered to be sufficiently stable. Parents or guardians will be given an information sheet in their usual language containing details of the FEAST trial. The sheet will be read aloud to those who are unable to read. Parents and guardians will be encouraged to ask questions about the trial prior to signing the consent form. (See Appendix 2.0 for Patient Information sheet and consent form). 9.2 Emergency verbal assent followed by deferred consent Verbal assent will be sought from parents or guardians by the admitting medical team if (See Appendix 1.0 for consent procedures) it is considered that the full consent process would significantly delay treatment allocation, and consequently be detrimental to the child s health. Full consent will be sought once the child s clinical condition has been stabilized. Caregivers will be provided with a brief verbal description of the trial and will be given the opportunity to opt out of clinical research. The clinician will later sign the verbal assent form which will be filed with the consent form. If consent is withdrawn later no data from the subject will be used (Appendix 2.0 Template assent and consent form). Considerations for the emergency consent procedures are covered in the Ethical issues (Section 18.1) and in the Appendix Randomisation codes Cards with details of treatment allocation (saline, HAS or control) will be kept in consecutively numbered, sealed opaque envelopes, each signed across the seal. The cards will be kept two locked boxes, labeled FEAST A and FEAST B. All children in hypotensive shock at the time of admission will be assigned to FEAST B. All other children will be assigned to FEAST A. The cards for each trial group will be numbered consecutively and will be opened in numerical order. The randomisation list and envelopes will be prepared before the trial by the MRC CTU in London, and the list kept at the MRC CTU. The number of each envelope will be entered into a recruitment log before being opened. The card inside will direct the clinician to a separate, sealed trial box, kept in a locked filing cabinet on the admission ward, and containing the case record form (CRF) and the assigned intervention fluid. The intervention fluids for the trial plus dedicated administration sets will FEAST Page th Jan 2009 version 1.2

26 be kept in a locked cupboard, together with a fluid accountability log. The appearance of the trial fluids will be made distinct from those used in general clinical practice, so that their use outside of the trial can be easily detected. 10. TREATMENTS Children will be divided into 2 groups (FEAST A & FEAST B) on the basis of admission blood pressure (see Trial Design). Children with hypotensive shock (clinical signs of impaired perfusion PLUS severe hypotension*) will be assigned to FEAST B. * Severe hypotension: children <12 months: systolic blood pressure (BP) <50mmHg; 12 months to 5 years: systolic BP <60mmHg; >5 years: systolic BP <70mmHg Treatment Arms I. FEAST A: Intravascular volume depletion All children EXCEPT those with hypotensive shock on admission These children will be randomly allocated on a 1:1:1 basis to receive one of the following: Saline: Intravenous infusion of 0.9% saline 20mls/kg over one hour Albumin: Intravenous infusion of 5% human albumin solution (HAS) 20mls/kg over one hour Control: Maintenance fluids only with no additional bolus infusion At one hour Clinical assessment: vital signs (heart rate, respiratory rate, oxygen saturation, BP) plus assessment of perfusion and conscious level. a. Children in the saline or HAS intervention arm with persisting signs of impaired perfusion will receive a second infusion of 20mls/kg over one hour of saline or HAS. b. Children in the saline or HAS arm without features of impaired perfusion will NOT receive a second infusion of saline or HAS, will receive intravenous maintenance fluids until able to tolerate and retain oral fluids and/or feeds. c. Children in the control arm - no additional fluid bolus d. Any child who develop hypotensive shock (severe hypotension see definition) will receive a 40ms/kg bolus infused over one hour*., as follows: FEAST Page th Jan 2009 version 1.2

27 i. Children in the saline or HAS intervention arm with hypotensive shock at one hour will receive 40mls/kg designated fluid (saline or HAS) over one hour in preference to 20mls/kg. ii. Children in the control arm who develop hypotensive shock (severe hypotension see definition) will receive a rescue bolus of 0.9% saline 40ms/kg infused over one hour. e. Children undergoing or awaiting blood transfusion who have been randomised to saline or HAS will complete their initial infusion of saline or HAS but will NOT receive a second infusion. f. Children randomised to saline or HAS who develop signs suggestive of pulmonary oedema (oxygen saturation <90%, bilateral basal crepitations and increasing respiratory rate) and/or signs suggestive of raised intracranial pressure (unequal papillary response to light or Cushing s triad (systolic blood pressure BP> 90 th centile for age, relative bradycardia, irregular respiratory pattern)) will receive appropriate treatment (see under non-trial treatment) and will NOT receive further boluses of saline or HAS. g. Children with evidence of a definite or probable allergic reaction to HAS will, if clinically indicated, receive 0.9% saline instead of HAS. Mild allergic reaction: fever, chills, flushing, angio-oedema, pruritic rash, nausea and vomiting Severe allergic reaction: one of the above plus evidence of cardiovascular compromise (severe tachycardia and/or hypotension) or new respiratory features (wheeze, dyspnoea, or hypoxia). Severe tachycardia: <12 months: >180bpm; 12 months to 5 years: >160bpm; >5 years: >140 bpm Severe hypotension: children <12 months: systolic blood pressure (BP) <50mmHg; 12 months to 5 years: systolic BP <60mmHg; >5 years: systolic BP <70mmHg. All children will also commence standard treatment for their underlying illness (see under Non-trial treatment). II. FEAST B: Children with decompensated hypotensive shock on admission Eligible children with decompensated hypotensive shock (impaired perfusion plus severe hypotension) at the time of admission will not enter the control arm of the trial, but will be randomly assigned to receive volume expansion with either: c) Saline: Intravenous infusion of 0.9% saline 40mls/kg over one hour* d) Albumin: Intravenous infusion of 5% human albumin solution (HAS) 40mls/kg over one hour* *Saline or HAS 40mls/kg over one hour will be given to this critically ill group of children with an increased risk of mortality. *Children awaiting blood transfusion will receive 20ml/kg of saline or HAS, and if blood is available within the hour then will receive the remaining 20 mls/kg as whole blood. If blood is not available then remainder will be given as intervention fluid. FEAST Page th Jan 2009 version 1.2

28 At one hour Clinical assessment: vital signs (heart rate, respiratory rate, oxygen saturation, BP) plus assessment of peripheral perfusion and conscious level. a. Children with persistent hypotensive shock will receive a second bolus of 40 mls/kg of the designated fluid (saline or HAS), infused over one hour. b. Children with clinical signs of impaired perfusion but without hypotension will receive an infusion of 20mls/kg of the designated fluid (saline or HAS), infused over one hour. c. Children without persisting features of hypotension or impaired perfusion will NOT receive a second infusion of saline or HAS, but will receive intravenous maintenance fluids until able to tolerate and retain oral fluids and/or feeds. d. Children undergoing or awaiting blood transfusion will not receive a further infusion of saline or HAS, unless they have signs of hypotensive shock. Blood will be given as soon as it becomes available. e. Children without features of impaired perfusion will be changed to intravenous maintenance fluids until able to tolerate and retain oral fluids and/or feeds. f. Children who develop signs suggestive of pulmonary oedema (oxygen saturation <90%, bilateral basal crepitations and increasing respiratory rate) and/or signs suggestive of raised intracranial pressure (unequal pupils or Cushing s triad (systolic blood pressure BP> 90 th centile for age, relative bradycardia, irregular respiratory pattern)) will be managed appropriately (see under non-trial treatment) and will NOT receive further infusions of saline or albumin. g. Children with evidence of an allergic reaction to HAS will receive infusion(s) of 0.9% saline instead of HAS, if clinically indicated (see above) Mild allergic reaction: fever, chills, flushing, angio-oedema, pruritic rash, nausea and vomiting Severe allergic reaction: one of the above plus evidence of cardiovascular compromise (severe tachycardia and/or hypotension) or new respiratory features (wheeze, dyspnoea, or hypoxia). Severe tachycardia: <12 months: >180bpm; 12 months to 5 years: >160bpm; >5 years: >140 bpm Severe hypotension: children <12 months: systolic blood pressure (BP) <50mmHg; 12 months to 5 years: systolic BP <60mmHg; >5 years: systolic BP <70mmHg. All children will also commence standard treatment for their underlying illness (see under Non-trial treatment) Post admission- all arms After the first two hours of admission the ONLY indication for extra volume resuscitation that is permissible within the protocol will be the development of hypotensive shock. However, at centres FEAST Page th Jan 2009 version 1.2

29 where children are catheterized and urinary output measured reliably then extra volume resuscitation can be given to cases in whom oliguria is demonstrated (urine output of < 1 ml/kg/hour on two separate hours) in association with signs of impaired perfusion. The maximum total volume of resuscitation fluid for any child (regardless of arm) that is permissible within the protocol is 80mls/kg/day. (Note that this fluid is given IN ADDITION to standard maintenance fluids). Children who fail to respond to 80mls/kg/day of additional fluid may have fluid-refractory shock, and administration of further fluids in the absence of other supportive treatments (inotropes) is likely to be of limited value Non-trial treatment All trial patients will receive intravenous antibiotics. Children with proven malaria parasitaemia will receive treatment with antimalarial drugs. Intravenous maintenance fluids will be given until the child is able to drink and retain oral fluids. Antipyretics, anticonvulsants and treatment for hypoglycaemia will be administered according to nationally agreed protocols. Children with Hb <4g/dl (or Hb < 5 gl/dl and respiratory distress) will be transfused with 20mls/kg of whole blood Medications not permitted The use of Ringers Lactate and Darrow s solution (crystalloid volume expanders) will be strictly prohibited in trial participants. Use of diuretics during blood transfusion will be limited to children with clinical evidence of pulmonary oedema (oxygen saturation <90%, plus bilateral basal crepitations). Experimental therapies given to treat metabolic acidosis (e.g. sodium bicarbonate, N-acetyl cysteine) will not be permitted in the trial protocol. The only exception will be situations in which there is definitive evidence of severe salicylate toxicity (salicylate level > 50mg/l), when sodium bicarbonate may be used to alkalinise the urine. Concomitant medication with doses will be recorded on the case record form. 11. TRIAL PRODUCTS 11.1 Description Normal Saline (0.9%) Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition: 0.9% Sodium Chloride Injection, USP contains 9 g/l Sodium Chloride USP (NaCl) with an osmolarity of 308 mosmol/l (calc). It contains 154 meq/l sodium and 154 meq/l chloride. The ph is 5.5 (4.5 to 7.0). Human Albumin Solution (HAS) 5% Albumin Solution (Baxter) is a sterile, nonpyrogenic preparation of albumin in a single dosage form for intravenous administration. It is packaged in packaged in glass bottles of 250mls or 500mls. Each 100 ml contains 5 g of albumin and is prepared from human venous plasma using the Cohn cold ethanol fractionation process. Source material has been obtained from U.S. licensed manufacturers. It has been adjusted to physiological ph with sodium bicarbonate and/or sodium FEAST Page th Jan 2009 version 1.2

30 hydroxide and has been stabilized with sodium caprylate and sodium acetyltryptophanate. The sodium content is 145 ± 15 meq/l. The solution contains no preservative and none of the coagulation factors found in fresh whole blood or plasma. 5% Human Albumin Solution is a transparent or slightly opalescent solution which may have a greenish tint or may vary from a pale straw to an amber color. The likelihood of the presence of viable viruses has been reduced by heating the product for 10 hours at 60 C. To date there have been no reported cases of hepatitis B (HBV), hepatitis C (HCV) or human immunodeficiency virus (HIV) associated with albumin therapy. Although the risk of viral transmission with albumin therapy cannot be completely eliminated, steps taken during the collection of source plasma and processing minimize the risk. First, source plasma donations are only accepted from repeat donors who do not demonstrate high risk behavior. Repeat donors have been noted to have lower rates of viral infection than do those donating for the first time. Second, donated blood istested for serologic viral markers. Third, plasma fractionators hold all donations for 60 days in order to detect seroconversion of HIV, HBV and HCV in recently infected donors. Finally, albumin undergoes heat pasteurization (see above) to inactivate viruses. This procedure has been shown to be an effective method of inactivating hepatitis virus in albumin solutions even when those solutions were prepared from plasma known to be infective. No specific interactions of human albumin with other medicinal products are known. 5% Albumin Solution (Baxter) has received Food and Drugs administration (FDA) approval for use for the following indications hypovolaemia (restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated), albumin replacement for hypo-albuminaemia and for burns (in conjunction with crystalloid therapy) Storage conditions Contains no preservative. To be stored at room temperature and should not to exceed 30 C (86 F). Can be stored in these conditions for three years as packaged. Single dose containers. Partially-used bottles to be discarded Accountability The trial coordinator (TC) will maintain accountability logs for both HAS and saline. A record will be kept of the empty fluid bottles and of unused trial fluids. This will kept securely until verified by the external monitor s visit Measures of compliance Lack of patient compliance will not be a major issue, since all children entering this trial will be critically ill and medical personnel will be responsible for administering the interventions. FEAST Page th Jan 2009 version 1.2

31 12 ASSESSMENTS AND FOLLOW-UP Procedure Assessment Time Admission 1hr 4hr 8hr 24hr 48hr Discharge 28 days 6 months Clinical assessment Laboratory tests X X X X X X X X X X X X Stored blood X X X Neurological exam X X X CRF X X X X X X X X X Quality of Life X All children (in FEAST A and FEAST B) will be reassessed clinically at 4, 8, 24 and 48 hours. Further infusions of saline or HAS will be given in accordance with the indications defined in Section No crossover of fluids between the saline and HAS arms of the trial will be permitted Follow up and loss to follow up Children will be assessed for neurological deficit at 28 days and six months (for those with persistent sequelae at 28 days from randomisation). Neurological assessments, which will be recorded on a standard proforma, will be carried out by a clinician or nurse who is blind to treatment allocation. Loss to follow up will not affect assessment of the primary outcome (in-hospital death at 48 hours), since most fatalities occur within 24 hours of hospital admission. Good compliance with assessment of neurological sequelae at 28 days and 6 months is anticipated, as families will be provided with cash to cover local transport costs Data for cost effectiveness analysis The research team will complete, shortly after admission, an additional questionnaire to help determine cost economic analysis. The cost-effectiveness of volume expansion will be estimated by comparing clinical outcomes and costs for children receiving any of the three treatments. Resource utilisation data including drug therapy, investigations, duration of inpatient stay and number of outpatient visits will be recorded prospectively through case record forms and chart review. Resource implications of neurological sequelae will be estimated in partnership with local clinicians. Unit cost data for these resources will be measured in collaboration with local investigators and the MRC Clinical Trials Unit. Resource utilisation data will be combined with unit cost data to estimate FEAST Page th Jan 2009 version 1.2

32 the total cost of adopting each treatment strategy as standard of care in this population, and to populate a Markov model of the cost-effectiveness of each intervention expressed as cost per life year saved and cost per disability adjusted life year (DALY) averted. Socioeconomic data on children and their families will also be collected Quality of life questionnaire For those will neurological impairment at 6 months the research nurse will approach parents to complete a quality of life questionnaire. This will be completed in the presence of the research nurse. 13. SAFETY REPORTING 13.1 Definitions Adverse Event (AE): any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product (IMP), whether or not considered related to the IMP. Adverse Reaction (AR): all untoward and unintended responses to an IMP related to any dose administered. All AEs judged by either the reporting investigator or the sponsor as having reasonable causal relationship to a medicinal product qualify as adverse reactions. The expression reasonable causal relationship means to convey in general that there is evidence or argument to suggest a causal relationship. Unexpected Adverse Reaction: an AR, the nature or severity of which is not consistent with the applicable product information (e.g. investigator s brochure for an unapproved investigational product or summary of product characteristics (SmPC) for an authorised product). When the outcome of the adverse reaction is not consistent with the applicable product information this adverse reaction should be considered as unexpected. Side effects documented in the SmPC which occur in a more severe form than anticipated are also considered to be unexpected. Serious Adverse Event (SAE) or Serious Adverse Reaction: any untoward medical occurrence or effect that at any dose Results in death Is life-threatening refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe Requires hospitalisation, or prolongation of existing inpatients hospitalisation Results in persistent or significant disability or incapacity Medical judgement should be exercised in deciding whether an AE/AR is serious in other situations. Important AE/ARs that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above, should also be considered serious. FEAST Page th Jan 2009 version 1.2

33 Suspected Unexpected Serious Adverse Reaction (SUSAR): any suspected adverse reaction related to an IMP that is both unexpected and serious Causality The assignment of the causality should be made by the investigator responsible for the care of the participant using the definitions in the table below. If any doubt about the causality exists the local investigator should inform the study coordination centre who will notify the Chief Investigators. Other clinicians may be asked to advise in some cases. In the case of discrepant views on causality between the investigator and others, all parties will discuss the case. Relationship Unrelated Unlikely Possible Probable Definitely Not assessable Description There is no evidence of any causal relationship There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the participant s clinical condition, other concomitant treatment). There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the participant s clinical condition, other concomitant treatments). There is evidence to suggest a causal relationship and the influence of other factors is unlikely. There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out. There is insufficient or incomplete evidence to make a clinical judgement of the causal relationship Reporting Procedures All relevant adverse events are reported in the case report form (CRF) and SAE form. The reporting procedure is captured within the safety reporting SOP. Any questions concerning adverse event reporting should be directed to the study coordination centre in the first instance. (This is done either via FEASTSAE@kilifi.kemri-wellcome.org or by telephone) Non serious AR/AEs At each clinical review the child is assessed for adverse experiences, whether expected or not. Nonserious and expected are captured in the CRF. All CRFs will be sent to the study coordination centre within one month of being completed Serious AR/AEs Fatal or life threatening SAEs and SUSARs should be reported on the day that the local site is aware of the event. The SAE form asks for nature of event, date of onset, severity, corrective FEAST Page th Jan 2009 version 1.2

34 therapies given, outcome and causality (i.e. unrelated, unlikely, possible, probably, definitely). The responsible investigator should sign the causality of the event. Additional information should be sent within 5 days if the reaction has not resolved at the time of reporting SAEs An SAE form should be completed and faxed to the FEAST study coordination centre for all SAEs within 24 hours. However, relapse, death or hospitalisations for elective treatment of a pre-existing condition do not need reporting as SAEs SUSARs In the case of serious, unexpected and related adverse events, the staff at the site should: Complete the SAE case report form & send it immediately (within 24 hours, by ), signed and dated to the study coordination centre together with relevant treatment forms and anonymised copies of all relevant investigations. Or Contact the study coordination centre by phone and then send the completed SAE form to the study coordination centre within the following 24 hours as above. Investigators are responsible for reporting any Serious Adverse Event, irrespective of whether it is defined as a SUSAR or a SAE immediately to the FEAST trial management team on FEASTSAE@kilifi.kemri-wellcome.org. The trial management team then have the responsibility of reporting on those defined as SUSARs to the sponsor, steering committee, national ethics committee and DSMB, as defined in the Safety reporting SOP. The study coordination centre will notify the main REC of all SUSARs occurring during the study according to the following timelines; fatal and life-threatening within 7 days of notification and non-life threatening within 15 days. All investigators will be informed of all SUSARs occurring throughout the study if they adversely affect the safety of any ongoing or potential trial subjects. This is the responsibility of the DSMB to decide and report. Local investigators should report any SUSARs and /or SAEs as required by their Local Research Ethics Committee and/or Research & Development Office. Contact details for reporting SAEs Please send SAE forms to: FEASTSAE@kilifi.kemri-wellcome.org Tel: or TRIAL CLOSURE The trial will be considered closed when the sample size has been achieved and six-month follow up of all children with neurological sequelae has been completed. FEAST Page th Jan 2009 version 1.2

35 15. WITHDRAWAL OF PATIENTS In consenting to the trial, patients are consenting to trial treatment, data collection and follow-up. If a patient wishes to withdraw from trial treatment, the investigator will explain the importance and benefits of follow-up, and the value of allowing routine clinical data to be used for trial purposes. Withdrawal from the intervention or control arms is unlikely, given that most interventions are given within the first 2 hours of admission. Severe allergic reaction (toxicity) is included as a secondary endpoint and is relevant only to children receiving human albumin solution (HAS). Global data on allergic reactions suggest that this is a rare event. It will not be a reason to withdraw the child from the trial, but further boluses of HAS should be withheld and 0.9% saline given instead, if further intervention is required for the treatment of hypotensive shock. 16. TRIAL MONITORING This trial will be monitored according to a monitoring SOP which will set out the frequency of visits, the degree of source document verification against the case record forms. A standard form will be used across all the sites for monitoring visits and these will be reviewed by the trial management group. The trial monitoring team will consist of the Kemri-Wellcome Clinical trial facility monitoring team and the MRC CTU who will provide over-site and some visits to maintain the integrity of the monitoring. The Clinical Trial Facility in Kilifi overseas standards and quality of all trials conducted through the KEMRI-Wellcome programme and through its monitoring systems and SOP s is organised to ensure that all sites, including Kilifi can be monitored with equal independence and rigor. All monitors will be appropriately qualified and trained. 17. CO-ENROLMENT Two of the five sites (Kilifi District Hospital, Kilifi Kenya and Teule Hospital, Tanzania) are involved in a multi-centre open Phase III trial comparing intravenous artesunate and quinine (AQUAMAT; ISRCTN Sponsor Oxford University PI Professor Nick White). Enrolment to AQUAMAT started in Kilifi in April 2006, and in Muheza in January 2007, and is expected to continue until August 2009 (See Appendix 3.1 for AQUAMAT summary). All children with confirmed severe malaria, irrespective of diarrhoeal illness or nutritional status, are eligible for co-enrolment in the AQUAMAT trial. If consent is refused, then children will be not enrolled into either trial and will receive standard care. Co-enrolment into both trials will not affect the outcome of either trial, since there are no known or anticipated interactions between the interventions being assessed in the two trials. Co-enrolment to clinical trials that include interventional medications known to cause hypotension will not be permitted, since this will confound interpretation of the trial results. FEAST Page th Jan 2009 version 1.2

36 18. ETHICAL CONSIDERATIONS 18.1 Emergency consent process In situations where research involves provision of emergency medical treatment it is often impracticable, or meaningless, to attempt immediately to obtain informed consent. Moreover, in situations where there is clinical equipoise then the subject is not worse off by enrolling. The decision to defer consent will be based upon the following guideline for assessment of competence or practicality of obtaining consent (and will be specifically covered in the pre-trial training and is specified in the Manual of Operations). If the child dies before consent is obtained, parents will not be asked for retrospective consent. The patient data will be included in the trial analysis, since it is likely to be highly informative. Four scenarios are envisaged: Scenario Degree of emergency Intervention Consent status Decompensated shock Pre-terminal FEAST B: Saline or HAS Deferred Intravascular volume Immediate resuscitation FEAST A: Deferred depletion :other life threatening Saline, HAS or complications e.g. seizures, control hypoglycaemia, hypoxia Intravascular depletion Intravascular depletion volume volume No other life threatening complications: parent able to receive and understand information No other life threatening complications: guardian or parent not available or; parent or guardian unable to receive or understand information. FEAST A: Saline, HAS or control FEAST A: Saline, HAS or control Prospective consent Deferred 18.2 Ethical approval The Study Coordination Centre has obtained approval from the Imperial Research Ethics Committee. However, the FEAST Trial Centre/ MRC CTU should receive copies of Local/National ERC approval and of the Patient information sheet and Consent Form on local headed paper before any patients are entered into the trial. For each patient, consent to participate in the trial should be obtained after all treatment options have been fully explained. The right of the patient to refuse participation in the trial must be respected. After the patient has entered the trial, the clinician should remain free to give alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the best interest of the patient. However, the reason for doing so should be recorded, and the patient will remain within the trial for the purposes of follow-up and data analysis. Similarly, the patient should remain free to withdraw at any time from the protocol treatment and trial follow-up, without giving reasons and without prejudicing his/her further treatment. FEAST Page th Jan 2009 version 1.2

37 19. TRIAL COMMITTEES 19.1 Trial management group A FEAST Trial Management Group (TMG) will be appointed and will be responsible for overseeing the progress of the trial. The day-to-day management of the trial will be coordinated through the Kilifi Study Coordination Centre Trial Steering Committee The trial will be managed by a Trial Steering Committee (TSC) with an independent chairperson (Professor Elizabeth Molyneux OBE), a majority of independent members and one Principal Investigator or key investigator from each of the sites, from Imperial College, and from MRC CTU Independent Data Monitoring Committee An independent Data Monitoring Committee (IDMC) will be set up to review data on enrolment, safety, adherence to randomised strategies, efficacy and safety at regular intervals and in strict confidence. At least 3 interim reviews (after 300, 600 and 900 patients have been enrolled) will be held during the trial. The IDMC will report to the Trial Steering Committee (TSC) and to the Ethics Committee in each country, if, in their view, the data provide proof beyond reasonable doubt that one of the allocated strategies is better than its comparator in terms of the primary outcome. The TSC will then decide whether to amend (which may include removing one of the intervention arms) or stop the trial before the end of the planned follow-up. If a decision is made to continue, the IDMC will advise on the frequency of future reviews of the data on the basis of accrual and event rates. The IDMC will make recommendations to the FEAST Trial Steering Committee as to the continuation of the trial Endpoint Review Committee An Endpoint Review Committee will review clinical data (blinded to allocation) and will determine the validity of potential endpoints. It will have an independent Chair and will the include Project Leaders from each site as well as other independent clinicians. No member will review endpoints from their own site. Terms of reference for the Endpoint Review Committee will be drawn up. 20. PUBLICATIONS The results from different centres will be analysed together and will be published as soon as possible. Individual clinicians must delay publication of data that are directly relevant to the questions posed by the study until the Trial Management Group has published its report. The Trial Management Group will form the basis of the Writing Committee, and will advise on the nature of publications. Members of the TMG will be listed, and contributors will be cited by name, provided that this does not conflict with journal policy. Members of the TSC and IDMC, together with their affiliations, will be listed in the Acknowledgements/Appendix of the main publication, where this does not conflict with journal policy. Authorship of parallel studies initiated outside of the Trial Management Group will be determined by the individuals involved in the project, but must FEAST Page th Jan 2009 version 1.2

38 acknowledge the contribution of the Trial Management Group and the FEAST Study Coordination Centre. The ISRCTN allocated to the trial should be attached to any publications resulting from this trial. FEAST Page th Jan 2009 version 1.2

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41 [49] Taylor TE, Molyneux ME, Wirima JJ, Fletcher KA, Morris K. Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria. N Engl J Med Oct 20;319(16): [50] Hall AP. The treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg. 1977;71(5): [51] Severe and complicated malaria. World Health Organization, Division of Control of Tropical Diseases. Trans R Soc Trop Med Hyg. 1990;84(Suppl 2):1-65. [52] English M, Waruiru C, Amukoye E, Murphy S, Crawley J, Mwangi I, et al. Deep breathing in children with severe malaria: indicator of metabolic acidosis and poor outcome. Am J Trop Med Hyg. 1996;55(5): [53] Bojang KA, Van Hensbroek MB, Palmer A, Banya WA, Jaffar S, Greenwood BM. Predictors of mortality in Gambian children with severe malaria anaemia. Ann Trop Paediatr. 1997;17(4): [54] Maitland K, Pamba A, Newton CR, Levin M. Response to volume resuscitation in children with severe malaria. Pediatr Crit Care Med Oct;4(4): [55] English M, Sauerwein R, Waruiru C, Mosobo M, Obiero J, Lowe B, et al. Acidosis in severe childhood malaria. QJMed. 1997;90(4): [56] Evans JA, May J, Ansong D, Antwi S, Asafo-Adjei E, Nguah SB, et al. Capillary refill time as an independent prognostic indicator in severe and complicated malaria. J Pediatr Nov;149(5): [57] Planche T, Onanga M, Schwenk A, Dzeing A, Borrmann S, Faucher JF, et al. Assessment of Volume Depletion in Children with Malaria. Plos Med ;1(1):e18. [58] Planche T. Malaria and fluids - balancing acts. Trends Parasitol. 2006;21: [59] WHO guidelines for the treatment of malaria. Geneva: World Health Organization; Report No.: ISBN [60] English M. Life-threatening severe malarial anaemia. Trans R Soc Trop Med Hyg. 2000;94(6): [61] Taylor TE, Borgstein A, Molyneux ME. Acid-base status in paediatric Plasmodium falciparum malaria. Q J Med. 1993;86(2): [62] Hospital Care for Children: guidelines for the management of common illnesses with limited resources.. Geneva, Switzerland: World Health Organization.; Report No.: ISBN [63] Tamburlini G, Di Mario S, Maggi RS, Vilarim JN, Gove S. Evaluation of guidelines for emergency triage assessment and treatment in developing countries. Arch Dis Child Dec;81(6): [64] Maitland K, Pamba A, English M, Peshu N, Levin M, Marsh K, et al. Pre-transfusion management of children with severe malarial anaemia: a randomised controlled trial of intravascular volume expansion. Br J Haematol Feb;128(3): [65] Maitland K, Pamba A, English M, Peshu N, Marsh K, Newton CRJC, et al. Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis Feb;40: [66] Akech S, Gwer S, Idro R, Fegan G, Eziefula AC, Newton CR, et al. Volume Expansion with Albumin Compared to Gelofusine in Children with Severe Malaria: Results of a Controlled Trial. PLoS Clin Trials Sep 15;1(5):e21. [67] Dubois MJ, Vincent JL. Use of albumin in the intensive care unit. Curr Opin Crit Care Aug;8(4): [68] Herson VC, Todd JK. Prediction of morbidity in Hemophilus influenzae meningitis. Pediatrics. 1977;59(1):35-9. [69] Powell KR, Sugarman LI, Eskenazi AE, Woodin KA, Kays MA, McCormick KL, et al. Normalization of plasma arginine vasopressin concentrations when children with meningitis are given maintenance plus replacement fluid therapy. J Pediatr. 1990;117(4): [70] Advanced Paediatric Life Support: The Practical Approach. 3rd ed. London: BR MED J Publishing Group [71] Slutsker L, Taylor TE, Wirima JJ, Steketee RW. In-hospital morbidity and mortality due to malariaassociated severe anaemia in two areas of Malawi with different patterns of malaria infection. Trans R Soc Trop Med Hyg Sep-Oct;88(5): FEAST Page th Jan 2009 version 1.2

42 [72] Lackritz EM, Campbell CC, Ruebush TK, 2nd, Hightower AW, Wakube W, Steketee RW, et al. Effect of blood transfusion on survival among children in a Kenyan hospital. Lancet. 1992;340(8818): [73] Marsh K, Forster D, Waruiru C, Mwangi I, Winstanley M, Marsh V, et al. Indicators of life-threatening malaria in African children. N Engl J Med. 1995;332(21): [74] English M, Ahmed M, Ngando C, Berkley J, Ross A. Blood transfusion for severe anaemia in children in a Kenyan hospital. Lancet. 2002;359(9305): [75] Newton CR. Interaction between Plasmodium falciparum and human immunodeficiency virus type 1 on the central nervous system of African children. Journal of neurovirology. 2005;11 Suppl 3: [76] Kublin JG, Patnaik P, Jere CS, Miller WC, Hoffman IF, Chimbiya N, et al. Effect of Plasmodium falciparum malaria on concentration of HIV-1-RNA in the blood of adults in rural Malawi: a prospective cohort study. Lancet Jan 15;365(9455): [77] Whitworth JA, Hewitt KA. Effect of malaria on HIV-1 progression and transmission. Lancet Jan 15;365(9455): [78] Waterlow J. Treatment of children with malnutrition and diarrhoea. Lancet Oct 2;354(9185):1142. [79] Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. Bmj Jul 25;317(7153): [80] Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid resuscitation: a systematic review. Crit Care Med Jan;27(1): [81] Devlin JW, Barletta JF. Albumin for fluid resuscitation: implications of the Saline versus Albumin Fluid Evaluation. Am J Health Syst Pharm Mar 15;62(6): [82] Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med May 27;350(22): [83] Falk JL, Rackow EC, Weil MH. Colloid and crystalloid fluid resuscitation. Acute Care. 1983;10(2): [84] Roberts JS, Bratton SL. Colloid volume expanders. Problems, pitfalls and possibilities. Drugs May;55(5): [85] Emerson T. Unique features of albumin:a brief review. Crit Care Med. 1989;17(7): [86] Dung NM, Day NP, Tam DT, Loan HT, Chau HT, Minh LN, et al. Fluid replacement in dengue shock syndrome: a randomized, double-blind comparison of four intravenous-fluid regimens. Clin Infect Dis Oct;29(4): [87] Ngo NT, Cao XT, Kneen R, Wills B, Nguyen VM, Nguyen TQ, et al. Acute management of dengue shock syndrome: a randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis Jan 15;32(2): [88] Wills B, Nguven D, Loan H, Dong T, Tran T, Le M, et al. A randomised double blind comparison of Ringer-Lactate, Dextran and Starch solutions for resuscitation of Vietnamese children with Dengue Shock Syndrome. N Engl J Med [89] Juca CA, Rey LC, CV. M. Comparison between normal saline and a polyelectrolyte solution for fluid resuscitation in severely dehydrated infants with acute diarrhoea. Ann Trop Paediatrics Dec;25(4): [90] Upadhyay M, Singhi S, Murlidharan J, Kaur N, S. M. Randomized evaluation of fluid resuscitation with crystalloid (saline) and colloid (polymer from degraded gelatin in saline) in pediatric septic shock. Indian Pediatr Mar;42(3): [91] Wills BA, Oragui EE, Dung NM, Loan HT, Chau NV, Farrar JJ, et al. Size and charge characteristics of the protein leak in dengue shock syndrome. J Infect Dis Aug 15;190(4): [92] Phuong CX, Nhan NT, Kneen R, Thuy PT, van Thien C, Nga NT, et al. Clinical diagnosis and assessment of severity of confirmed dengue infections in Vietnamese children: is the world health organization classification system helpful? Am J Trop Med Hyg Feb;70(2): [93] Snow R, Craig H, Newton C, Steketee R. The public health burden of Plasmodium falciparum malaria in Africa: Deriving the numbers. Working Paper No. 11, Bethesda, Maryland: Fogarty International Center, National Institutes of Health; 2003 August FEAST Page th Jan 2009 version 1.2

43 [94] The prevention and management of severe anaemia in children in malaria-endemic regions of Africa. Geneva: World Health Organization; [95] Clinical Use of Blood in Medicine, Obstetrics, Paediatrics, Surgery & Anaesthesia, Trauma & Burns (The). Geneva: World Health Organization/Blood Transfusion Service; [96] Bojang KA, Palmer A, Boele van Hensbroek M, Banya WA, Greenwood BM. Management of severe malarial anaemia in Gambian children. Trans R Soc Trop Med Hyg. 1997;91(5): [97] Holzer BR, Egger M, Teuscher T, Koch S, Mboya DM, Smith GD. Childhood anemia in Africa: to transfuse or not transfuse? Acta Trop. 1993;55(1-2): [98] Obonyo CO, Steyerberg EW, Oloo AJ, Habbema JD. Blood transfusions for severe malaria-related anemia in Africa: a decision analysis. Am J Trop Med Hyg. 1998;59(5): [99] Binda ki Muaka P, Nzita M, Eeckels R. Malaria, anaemia, and HIV-1 transmission in central Africa. Lancet. 1995;346(8985): [100] Fleming AF. HIV and blood transfusion in sub-saharan Africa. Transfus Sci. 1997;18(2): [101] Global database of blood safety. Summary report Geneva: World Health Organization, Blood Transfusion Safety, Department of blood transfusion safety and clinical technology; [102] Colebunders R, Bahwe Y, Nekwei W, Ryder R, Perriens J, Nsimba K, et al. Incidence of malaria and efficacy of oral quinine in patients recently infected with human immunodeficiency virus in Kinshasa, Zaire. J Infect Sep;21(2): [103] Colebunders R, Greenberg AE, Francis H, Kabote N, Izaley L, Nguyen-Dinh P, et al. Acute HIV illness following blood transfusion in three African children. Aids Apr;2(2): [104] Jacobs B, Mercer A. Feasibility of hospital-based blood banking: a Tanzanian case study. Health Policy Plan. 1999;14(4): [105] Hensher M, Jefferys E. Financing blood transfusion services in sub-saharan Africa: a role for user fees? Health policy and planning Sep;15(3): [106] Planche T, Agbenyega T, Bedu-Addo G, Ansong D, Owusu-Ofori A, Micah F, et al. A prospective comparison of malaria with other severe diseases in African children: prognosis and optimization of management. Clin Infect Dis Oct 1;37(7): FEAST Page th Jan 2009 version 1.2

44 APPENDICES APPENDIX 1. CONSENT PROCEDURES Justification for emergency consenting procedure Situations where research involves provision of medical care in an emergency are usually viewed as a general exception to the requirement for prospective consent. If emergency care is to be improved, research is necessary. On many occasions it may be impracticable, or meaningless, to attempt to obtain immediate informed consent from parents or guardians. A proposed alternative to asking for parental consent is to place responsibility for ensuring that a study is ethical on the research and ethical committees. It is argued that this would provide the necessary assurance that the research study had been subject of careful and considered scrutiny by a group of informed objective professional and lay people. Also that taking part would not be against the child s best interests, and would provide the opportunity for critically-ill patients to access new, and potentially beneficial, therapies. This approach is supported by international documents i-iv and by guidelines developed especially for paediatric research. The 1997 FDA i guidelines outline the substantive requirements of emergency waiver or deferment of consent, namely: 1. The need is great because the subject s condition is life-threatening and the available treatment are unsatisfactory. 2. The risks to the subjects are reasonable in light of the potential benefits to the subjects 3. Consent cannot be obtained because of the subject s condition, time constraints and because potential subjects cannot be identified in advance. We believe that this is the case for the FEAST trial. Specifically, Requirements 1 and 3: many children entering the trial will have an acute, life-threatening illness. Many will be unconscious, fitting or have respiratory distress, and will require immediate resuscitation. Fluid resuscitation constitutes part of emergency management. In such circumstances, a full consent process would significantly delay treatment allocation, and would consequently be detrimental to the child s health, as well as causing undue anxiety to guardians. Requirement 2: the risk of fluid resuscitation for eligible children is minimal, which has been previous confirmed in 3 trials, whereas the potential benefit could be substantial. The Medicines and Healthcare products Regulatory Agency, UK (MHRA) is assessing new guidelines for clinical trials in emergency situations involving children, which would allow such trials to start without initial consent, so long as consent obtained as soon as reasonably practical. The Kenyan National guidelines iv state In emergency settings that preclude time for identifying and eliciting the consent of a proxy decision maker research can proceed without either informed consent or permission of proxy decision makers when conducted under strict guidelines. Most importantly, there should be clinical equipoise the absence of consensus regarding the comparative merits of the interventions to be tested. In such a case, the subject is not worse off by enrolling. Guidelines for deferred consent for FEAST trial FEAST Page th Jan 2009 version 1.2

45 The decision to defer consent will be based upon the following guideline for assessment of competence or practicality of obtaining consent (and will be specifically covered in the pre-trial training and is specified in the Manual of Operations). Four scenarios are envisaged: Scenario Degree of emergency Intervention Consent status Decompensated shock Pre-terminal FEAST B: Saline or HAS Waiver/ Deferred Compensated shock Immediate resuscitation FEAST A: Waiver/ Deferred :other life threatening Saline, HAS or complications e.g. seizures, control hypoglycaemia, hypoxia Compensated shock No other life threatening complications: parent able to receive and understand information Compensated shock No other life threatening complications: guardian or parent not available or; parent or guardian unable to receive or understand information. FEAST A: Saline, HAS or control FEAST A: Saline, HAS or control Prospective consent Waiver/ Deferred Consenting procedure For the majority of participants, prospective consent will be sought (Appendix 2.1 Template Patient Information sheet and consent form). For children requiring resuscitation or emergency treatments, who are likely to constitute approximately 30-40% of those eligible for the trial, we will defer full consent until parents are in a position to receive it (at which point full information will be given and parents/guardian s consent to proceed will be sought). In situations where consent is deferred, verbal information about the trial will be provided to the parents by a member of trial team, and parents will be asked to indicate whether they agree to the child taking part in the research study (Appendix 2.2 Template Assent Form). The doctor or nurse asking permission will then sign the assent form, and will indicate whether the guardian has assented to the research study. Full informed consent will be requested once the child s condition has been stabilised, emergency treatments have been administered, and parental ability to receive full information has been checked. This process will be described fully in the Manual of Operations. The patient information sheet will be read/read out and consent requested. If consent is refused, the patient s data will not be included in the study. If the child dies before consent is obtained, parents will not be asked for retrospective consent. The patient data will be included in the trial analysis, since it is likely to be highly informative. i. Guidelines for the ethical conduct of medical research involving children: Royal College of Paediatrics and Child Health: Ethics Advisory Committee (Arch Dis Child 2000; 82: ) ii. iii. iv. FDA website information for IRBs and clinical investigators ( Medicines and Healthcare products Regulatory Agency, UK Guidelines for Ethical Conduct of Biomedical Research Involving Human Subjects in Kenya, Nairobi 2004 FEAST Page th Jan 2009 version 1.2

46 APPENDIX 2. PATIENT INFORMATION SHEET AND CONSENT 2.1 Template Patient information sheet and consent Template Patient Information and Consent Form for FEAST (Fluid Expansion As Supportive Therapy in critically ill African children) Full title: A randomised trial of fluid resuscitation strategies in African children with severe febrile illness and clinical evidence of impaired perfusion What is this research about? Your child has a serious illness. In this research we aim to find out whether giving children with such symptoms additional fluid (administered intravenously) soon after admission will improve upon currently recommended treatment guidelines. The treatments used in this research are frequently used in sick children with good effect in other parts of the world. We want to see if they are helpful in African children. Since this is not known at the moment, we would like to learn this through allocating up to 2880 children aged 2 months to 12 years with these symptoms into one of three treatment groups: 1) Receiving nationally recommended treatment 2) Receiving recommended treatment but with an additional volume of fluid called albumin soon after admission. 3) Receiving recommended treatment but with an additional volume of fluid called saline soon after admission. Which of the three types of treatment a child is given will be decided by chance. What will it involve for me/my child? 1. For the children in the two groups receiving extra fluid, most of this will be given at the time your child is admitted. 2. All children will be closely watched to decide whether to make any changes to treatment or to prescribe more fluid. This monitoring will be through regular checks by the nurses. Currently, we are taking 1 teaspoon of blood at admission (4mls) as part of routine clinical care. In this study, we will take an additional teaspoon of blood on admission (4mls) and an extra half a teaspoon (2mls) at 24 and 48 hours after admission. 3. We will also check on your child s progress 28 days post admission, in the hospital clinic. This will include taking another small blood sample (half a tea spoon, 2 mls) from your child s arm. 4. Finally, we would like to store small amounts of each blood sample taken for future research. Are there any risks or disadvantages to me/my child of taking part? Fluid infusion has been used extensively in children in other parts of the world, and has been shown to be safe and to work well in the research already done. However, there is a very small chance that there may be a reaction we do not expect, but we will be monitoring your child very closely, and this is considered to be unlikely. If for any reason the doctor thinks that it is not in your child s best interest to be in the trial, then they will not be enrolled in the trial but will be given normal standard of care. There are no costs for being included in the trial. Are there any benefits to me/my child of taking part? Your child will get close observation during the trial, and by taking part your child may help us improve the care of children who have serious illness in the future. Regular assessment of your child by doctors and nurses and the additional blood will enable us to make important changes to your child s treatment in hospital, if necessary. We will ensure that all routine medications that the hospital needs to treat your child are made available. FEAST Page th Jan 2009 version 1.2

47 You will be asked to bring your child back for follow up, and we will pay for your transport from hospital to home and back to the clinic so you can attend this important visit. During the follow up visit will treat any illnesses we find. We will follow up any child with on going medical problems 6 months later. Transport costs for this visit will be also be reimbursed.. What will happen if I don t agree to participate? All participation in research is voluntary. You are free to decide if you want your child to take part or not. Your child will still receive the recommended standard of care if they do not take part. If you do agree you can change your mind at any time, and can withdraw your child from the research. This will not affect their care now or in the future. What happens to the samples? Some of the tests to find out what caused your child s illness are needed as part of this research cannot be done in (Kenya/Uganda /Tanzania) at the moment, so part of the samples will be sent to laboratories overseas. This will involve a small portion of the blood that was taken during the study, which we will store. Individual names will be removed and will be replaced by codes, so that information cannot be linked to participants. Any future research done on these samples must first be approved by a national independent expert committee, to ensure that participants safety and rights are respected. Who will have access to information about me/my child in this research? All our research records are stored securely in locked cabinets and password protected computers. Only a few people who are closely concerned with the research will be able to view information from participants. Who has allowed this research to take place? All research conducted in (Kenya/Uganda /Tanzania) is approved by national independent expert committees to make sure the research is conducted properly and that trial participants safety and rights are respected. What if I have any questions? You may ask any of our staff questions at any time. You can also contact those who are responsible for the care of your child and this research: Dr Address telephone If you want to ask someone independent anything about this research please contact Name Chairman National Ethics Review Committee Address telephone This research is supported by Imperial College London who hold insurance policies which apply to this trial. If you experience harm or injury as a result of taking part in this study, you will be eligible to claim compensation without having to prove that Imperial College is at fault. Some specific treatment and compensation are not included in our insurance policies and if you want more information about this you should discuss it with the doctor attending your child. FEAST Page th Jan 2009 version 1.2

48 Template Consent Form for FEAST (Fluid Expansion As Supportive Therapy in critically ill African children) This form should be completed after the patient information sheet has been read or read out. Site.. Child s Initials Male Female Date/Year of Birth D D M M M Y Y Y Y Age (years) Date of Form D D M M M 2 0 Y Y Clinic/Hospital Number I have read/been read the information sheet for the FEAST study. I have understood everything and have had my questions answered satisfactorily. I understand that I may change my mind at any stage and that this will not affect the benefits due to my child. I agree to allow my child to take part in the FEAST study I agree that the results of these tests, and any blood left over from them, may be kept by the FEAST team for further studies. I understand that these results and samples will not be identified by either my or my child s name. I agree to samples being exported overseas for further studies Carer s signature (or thumbprint) Print name Date D D M M M 2 0 Y Y Witness s signature (if thumbprint used above) Print name Date D D M M M 2 0 Y Y Doctor s or Nurse s signature Print name Date D D M M M 2 0 Y Y Note: One signed original to be kept in FEAST trial file by the researcher, one signed copy to be given to guardian, one signed copy to be kept in the clinic notes. FEAST Page th Jan 2009 version 1.2

49 2.2 Template Assent form Assent Form for FEAST (Fluid Expansion As Supportive Therapy in critically ill African children) Site.. Child s Initials Male Female Date/Year of Birth D D M M M Y Y Y Y Age (years) Date of Form D D M M M 2 0 Y Y Clinic/Hospital Number For children defined in the SOP as critically ill. Brief discussion with the parents/guardians by the admitting trial doctor or nurse should include the following phrases. We are going to provide the treatment for your child that is recommended by the government. We want to find out if we can improve on these current recommendations by trying new treatments that we think will work better and we do this by research. All research is checked by independent committees to make sure that the potential benefits to individuals outweigh the risks. All Participation in research is voluntary, and so you can refuse. We would like your child to participate in research for us to learn the best way to give fluids to very sick children. Do you agree for your child to take part in this research? You can say no and your child will still receive the same level of care with the governments recommended treatment. Doctor or nurses signature Print name Date D D M M M 2 0 Y Y Parent/Guardian assents to research? Yes / No FEAST Page th Jan 2009 version 1.2

50 APPENDIX 3. CO-ENROLMENT WITH AQUAMAT Considerations for co-enrolment There is no a priori evidence which might suggest an interaction, or rationale to hypothesise the existence of one. If, however, such an unexpected interaction did exist, with, for example, the fluid regimen altering the treatment effect in AQUAMAT, co-enrolment of the FEAST and AQUAMAT trials would provide a unique opportunity to uncover the interaction. Where no interaction is anticipated, co-enrolment only affects the power of study to show differences, and thus has implications for the size of each study. This will be of minor consequence for FEAST and AQUAMAT trials (see under Statistical considerations). Co-enrolment has been successfully employed in severe malaria studies in Africa before; in the largest published clinical trial in childhood severe malaria an artemether/quinine comparison coenrolled in a factorial design with an anti-tnf antibody/placebo comparison (van Hensbroek et al, N Engl J Med 1996, 335: 69-75, and van Hensbroek et al, J Infect Dis 1996; 174: ). Practical Considerations FEAST and AQUAMAT have different entry criteria and different a priori mortality in the groups eligible for entry (15-20% for FEAST and 8% for AQUAMAT). All children with severe malaria, irrespective of shock, haemoglobin or nutritional status are eligible for the AQUAMAT trial. In order simplify the recruitment process and expedite treatment, children entering the FEAST trial will be coenrolled into the AQUAMAT trial. The overlap is likely to be relatively small at both sites, and staff will be trained how to identify patients likely to be eligible for both studies. Children are only enrolled to AQUAMAT once a malaria diagnosis is secured and thus there is no provision for deferred consent. Children eligible for recruitment to the FEAST trial whose fluid intervention are allocated following verbal assent i.e. (emergency consent deferral) and in whom malaria status is subsequently will be eligible for both FEAST and AQUAMAT. For these children simultaneous prospective consent for both trials (FEAST and AQUAMAT) would occur shortly after admission, if declined then the child would not continue in either trial.. For children where prospective consent is appropriate in FEAST, rapid diagnostic testing for malaria will enable malaria (and thus eligibility for AQUAMAT) to be determined within 15 minutes. This would be is the approximate time it would take for consent process for FEAST and AQUAMAT. If consent were refused then the child would not enrolled into either trial and receive standard care. 3.2 Summary of AQUAMAT trial Aim: To compare the mortality and significant sequelae of severe falciparum malaria in African patients treated with intravenous quinine to those in patients treated with intravenous artesunate. FEAST Page th Jan 2009 version 1.2

51 Background: Severe malaria kills over one million African children each year. Parenteral quinine is the current treatment for in Africa, but in Asia artesunate was shown (SEAQUAMAT trial) to reduce the mortality of severe malaria by 35% compared with quinine and is now recommended by WHO. A meta-analysis of studies comparing artemether (a compound similar, but less well absorbed than artesunate) with quinine indicated that results in Asian adults differed from those in African children, so extrapolation from Asia to Africa may not be warranted. Yet pre-referral treatment with rectal artesunate in African children with severe malaria recently reduced mortality by 25%. Major objective: To determine in a definitive randomised trial whether parenteral artesunate reduces the mortality of severe malaria in African children. Design: An open, randomised trial comparing parenteral quinine and parenteral artesunate Inclusion criteria: Children aged 6 months and above with a clinical diagnosis of severe malaria; positive malaria antigen rapid test result (Optimal ) and written informed consent by patient or their attending relative Exclusion criteria: Known allergy to one of the artemisinin derivatives or quinine. History of treatment with quinine or artemisinin derivative for more than 24 hours before admission. Treatment: Children allocated treatment with either parenteral artesunate (2.4 mg/kg at admission, 12hrs, then daily) or parenteral quinine (loading dose 20 mg salt /kg, then 10 mg/kg q 8h). Outcome Primary: In-hospital mortality in children. Secondary: neurological sequelae noted at discharge and 1 and 6 month follow up, death plus sequelae, hypoglycaemia (glucose <2.2mmols/L); acute allergic reactions (requiring treatment) and any other severe and unexpected adverse event. Sample size: The aim will be to include 5,306 patients with severe malaria. This is based on the number needed to show a 25% reduction in mortality from 8% to 6% with a power of 80% and a confidence of 95%. FEAST Page th Jan 2009 version 1.2

52 FEAST Fluid Expansion As Supportive Therapy in critically ill African children Full study title: A randomised trial of fluid resuscitation strategies in African children with severe febrile illness and clinical evidence of impaired perfusion Protocol version 2.0 Jun 18 th, 2010 MAIN SPONSOR: Imperial College London FUNDERS: Medical Research Council STUDY COORDINATION CENTRE: KEMRI Wellcome Trust Research Programme Kilifi, Kenya ISRCTN ICREC_8_1_1 Protocol authorised by: Name: Professor Elizabeth Molyneux Role: Chair of Trial Steering Committee Date: Signature: FEAST Page 1 June 18, 2010 version 2.0

53 Study Management Group Chief investigator Professor Kathryn Maitland, KEMRI Wellcome Trust Unit, P.O Box , Kilifi, Kenya Tel ; Fax (alternative Principal co-investigators* and investigators * Principal co-investigators (one per site) are indicated in bold Professor Mike Levin, Imperial College London (St Mary s Campus), Norfolk Place, London W2 1PG, UK. m.levin@imperial.ac.uk; Tel: + 44 (0) ; Fax: +44 (0) Professor Diana Gibb MRC Clinical Trials Unit, 222, Euston Road, London NW1 2DA, UK. dmg@ctu.mrc.ac.uk; Tel: ; Fax: Dr Jane Crawley MRC Clinical Trials Unit, 222, Euston Road, London NW1 2DA, UK. jmc@ctu.mrc.ac.uk; Tel: ; Fax: Dr James Tibenderana, Malaria Consortium Africa Regional Office, Kampala, Uganda j.tibenderana@malariaconsortium.org Tel: Fax: Kenya Dr Samuel Akech, KEMRI-Wellcome Trust Programme, P.O Box , Kilifi, Kenya sakech@kilifi.kemri-wellcome.org; Tel ; fax Professor Charles Newton, KEMRI-Wellcome Trust Programme, P.O Box , Kilifi, Kenya. cnewton@kilifi.kemri-wellcome.org; Tel ; fax Tanzania Dr George Mtove, Joint Malaria Programme, Teule hospital, P.O Box 81, Muheza, Tanzania. gmtove@nimr.or.tz ; Tel / ; Fax Dr Hugh Reyburn, Joint Malaria Programme, P.O Box 2228, KCMC, Moshi, Tanzania hugh.reyburn@lshtm.ac.uk ; Tel ; Fax FEAST Page 2 June 18th 2010 version 2.0

54 Professor Chris Whitty, Joint Malaria Programme, LSHTM, Keppel St, London WCI1E 7HT, UK. Tel ; Fax Uganda Mulago Hospital, Kampala Professor Sarah Kiguli, Department of Paediatrics, PO Box 7072 Makerere University, Kampala, Uganda. ; Tel ; Fax Dr Robert Opoka, Consultant Paediatrician Tel ; Fax Dr Justus Byarugaba Senior Paediatrician Tel ; Fax Soroti Dr Charles Engoru, Soroti Regional Hospital, P.O Box 289 Soroti. Tel ; Fax Lacor, Gulu Dr Richard Nyeko, St Mary s Hospital, Lacor PO 180 Gulu Richard_nyeko@yahoo.com; Tel ; Fax Mbale Dr Peter Olupot 0lupot, Mbale Regional Referral Hospital, P.O Box 921, Mbale. polupotolupot@yahoo.com; Tel ; Fax FEAST Study investigators Dr Hans- Joerg Lang: Trial Paediatric Coordinator Dr Trudie Lang: Head of Kilifi Clinical Trials Facility Dr Greg Fegan: Senior Statistician Nicolette Davies: Trial Administrator, Imperial College hajoe123@yahoo.es tlang@kilifi.kemri-wellcome.org gfegan@kilifi.kemri-wellcome.org nicolette.davies@imperial.ac.uk Trial statistician Professor Abdel Babiker, MRC CTU, Euston Road London agb@ctu.mrc.ac.uk; Tel ; Fax FEAST Page 3 June 18th 2010 version 2.0

55 Trial Management Group Kilifi Clinical Trials Facility KEMRI Wellcome Trust Research Programme, P.O Box , Kilifi, Kenya Tel ; Fax Mukami Mbogo: FEAST Trial Manager Dr Chemtai Kipkeu: KCTF Project manager Gilbert Ogetii: FEAST Trial Monitor Naomi Waithira Data Manager: Statistician: (TBA) Study Coordination Centre For general queries, supply of trial documentation, and collection of data, please contact: Study Coordinator: Mukami Mbogo Address: KEMRI Wellcome Trust Programme, P.O Box , Kilifi, Kenya Tel: Fax: Clinical Queries Clinical queries should be directed to Mukami Mbogo (Telephone: or (mobile number to be added) who will direct the query to the appropriate person Sponsor Imperial College (St Mary s Campus), Norfolk Place, London W2 1PG, UK Funder Medical Research Council, 20 Park Crescent, London W1B 1AL, UK FEAST Page 4 June 18th 2010 version 2.0

56 General information This protocol describes the FEAST Trial on the recruitment and management of trial participants. Every care was taken in its drafting, but corrections or amendments may be necessary. Any changes will be defined as modifications or amendments. Any such changes will be coordinated by the trial management team, taken through any ethics review or notification and then new versions issues to each centre by the trial management group. Problems relating to this trial should be referred, in the first instance, to the study coordination centre. This trial will adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) and the International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines. It will be conducted in compliance with the protocol, the Data Protection Act and other regulatory requirements as appropriate. FEAST Page 5 June 18th 2010 version 2.0

57 Table of Contents STUDY SUMMARY INTRODUCTION TRIAL OBJECTIVES Primary objectives Secondary objectives TRIAL OUTCOME MEASURES Primary endpoints Secondary endpoints TRIAL DESIGN STATISTICAL CONSIDERATIONS Randomisation Sample size calculation Analysis Plan PATIENT POPULATION ELIGIBILITY Inclusion criteria Exclusion criteria SCREENING AND INVESTIGATIONS RANDOMISATION AND ENROLMENT TREATMENTS Treatment Arms Post admission- all arms Non-trial treatment TRIAL PRODUCTS ASSESSMENTS AND FOLLOW-UP Follow up and loss to follow up Data for cost effectiveness analysis Quality of life questionnaire SAFETY REPORTING Definitions Causality Reporting Procedures TRIAL CLOSURE WITHDRAWAL OF PATIENTS TRIAL MONITORING CO-ENROLMENT ETHICAL CONSIDERATIONS TRIAL COMMITTEES PUBLICATIONS REFERENCES APPENDICES APPENDIX 1. CONSENT PROCEDURES APPENDIX 2. PATIENT INFORMATION SHEET AND CONSENT APPENDIX 3. CO-ENROLMENT WITH AQUAMAT FEAST Page 6 June 18th 2010 version 2.0

58 GLOSSARY OF ABBREVIATIONS AE AR BP bpm CRF CRT CVP ERC HAS Hb HIV ICP IDMC ISRCTN KEMRI KCTF MOP MRC CTU PI PIS RCT RDT SAE Saline SAR SBP SMA SOP SSA SUSAR TMG TSC UAR U&E Adverse event Adverse reaction Blood pressure Beats per minute Case Report Form Capillary refilling time Central venous pressure Endpoint Review Committee 5% Human albumin solution Haemoglobin Human immunodeficiency virus Intracranial pressure Independent Data Monitoring Committee International standard randomised controlled trial number Kenya Medical Research Institute Kilifi Clinical Trials Facility Manual of operations Medical Research Council Clinical Trials Unit Principal Investigator Patient information Sheet Randomised controlled trial Rapid diagnostic test Serious adverse event 0.9% saline infusion Serious adverse reaction Systolic blood pressure Severe malarial anaemia Standard operating procedures Site specific assessment Suspected unexpected serious adverse reaction Trial Management Group Trial Steering Committee Unexpected adverse reaction Urea and electrolytes FEAST Page 7 June 18th 2010 version 2.0

59 GLOSSARY OF TERMS Coma Hypotensive shock Impaired perfusion Intravascular volume depletion Impaired consciousness Prostration Respiratory distress Inability to localize a painful stimulus Children with clinical signs of severe illness and impaired perfusion plus severe hypotension 1 of: capillary refill >2 seconds; lower limb temperature gradient; weak radial pulse volume; severe tachycardia Depletion of circulating volume : relative (due to vasodilatation) or actual (loss of fluid from intravascular space e.g. burns or blood loss or capillary leak) Prostration or coma Inability to sit unsupported, or to breast feed if <9 months Deep breathing or increased work of breathing Severe hypotension Systolic blood pressure <12 months: <50mmHg; 12 months to 5 years: <60mmHg; >5 years: <70mmHg Severe illness Children with impaired consciousness or respiratory distress Severe tachycardia Heart rate: <12 months: >180bpm; 12 months to 5 years: >160bpm; >5years: >140bpm KEYWORDS Children Infants Africa Kenya Tanzania Uganda Plasmodium falciparum malaria Sepsis Randomised controlled trial Human albumin solution Normal saline Fluid expansion Resuscitation Emergency medicine FEAST Page 8 June 18th 2010 version 2.0

60 STUDY SUMMARY TITLE: Fluid Expansion As Supportive Therapy in critically ill African children DESIGN A 3-arm randomised open comparative trial of fluid resuscitation strategies: (1) Immediate volume resuscitation with normal (0.9%) saline; (2) Immediate volume expansion with 5% human albumin solution (HAS); (3) Maintenance fluids, with no immediate volume expansion. AIMS In hospitals throughout sub-saharan Africa, mortality from malaria and other severe infections in childhood remains at 15-30%, with over 50% of deaths occurring within 24 hours of admission. Currently, antimalarial and antimicrobial drugs are the mainstay of treatment, with little consideration being given to the use of adjunctive supportive therapies. There is considerable debate about the degree to which intravascular volume depletion (hypovolaemia) contributes to the pathophysiology of malaria and other severe infections, and clinical practice varies widely across the continent. To resolve the continuing uncertainty, this multi-centre randomised clinical trial will evaluate different fluid resuscitation strategies in children presenting to hospital with severe febrile illness and clinical evidence of impaired perfusion, with the intention of generating data of practical value to clinicians working in resource-poor settings in Africa. OUTCOME MEASURES Primary Endpoint: In-hospital mortality at 48 hours after randomisation. Secondary Endpoints: Mortality at 4 weeks, neurological sequelae at 4 weeks and 24 weeks, episodes of hypotensive shock within 48 hours of randomisation, adverse events related to fluid resuscitation (pulmonary oedema, intracranial hypertension or severe allergic reaction to those receiving albumin). POPULATION Sample size The total sample size is 3600 children. Assuming that the background 48-hour mortality rate in the trial population is 11.4% and that 61% of eligible children will have P. falciparum parasitaemia (an important sub-group for which the trial will be adequately powered), the planned sample size will provide at least 80% power to detect a difference of 30% in 48- hour mortality between the saline and control arms and a difference of 40% between the HAS and saline arms, with type I error probability α = 0.05 and allowing for multiple comparisons. FEAST Page 9 June 18th 2010 version 2.0

61 ELIGIBILITY Inclusion criteria Children aged >60 days and <12 years with severe febrile illness (impaired consciousness or respiratory distress) plus clinical evidence of impaired perfusion. Exclusion criteria Children with the following conditions will be excluded: severe acute malnutrition; gastroenteritis; chronic renal failure, pulmonary oedema and other conditions in which volume expansion is contraindicated; non-infectious causes of severe illness; children who have already received an isotonic volume expander during the current illness. TRIAL TREATMENT 3600 eligible children will be randomly assigned in a ratio of 1:1:1 to one of three fluid management arms: (1) Rapid volume expansion with 40mls/kg intravenous 0.9% saline; (2) Rapid volume expansion with 40mls/kg 5% human albumin solution (HAS); (3) Maintenance fluids with no volume expansion (control arm). Children will be reassessed at 1, 4, 8, 24 and 48 hours, and further fluid boluses will be given in strict accordance with the protocol. Children will receive a maximum of 100mls/kg in 24 hours of fluid boluses. The small number of eligible children that are anticipated to have hypotensive shock (severe hypotension plus impaired perfusion) at the time of admission (n=144) will be randomly allocated in a ratio of 1:1 to rapid volume expansion with either saline or HAS. Follow-up Children will be clinically assessed at 1, 4, 8, 24 and 48 hours. Neurological assessments will be carried out at 4 weeks and, for those with sequelae at 4 weeks, at 24 weeks from the time of randomisation. Follow-up neurological assessments will be carried out by a clinician or nurse who is blind to treatment allocation. DURATION The trial will enrol over 30 months and started in January FEAST Page 10 June 18th 2010 version 2.0

62 Trial Schema FEAST Page 11 June 18th 2010 version 2.0