An Adaptive Multi-arm Trial to Improve Clinical Outcomes Among Children Recovering From Complicated SAM
- Conditions
- Comorbidities and Coexisting ConditionsSevere Acute MalnutritionChild MalnutritionHIV
- Interventions
- Other: Standard CareBehavioral: The Friendship BenchDietary Supplement: Reformulated Ready to Use Therapeutic FoodBehavioral: Care for Child DevelopmentBehavioral: Educational and behaviour-change modules
- Registration Number
- NCT05994742
- Lead Sponsor
- Queen Mary University of London
- Brief Summary
Malnutrition underlies 45% of child deaths, and has far-reaching educational, economic and health consequences. Severe acute malnutrition (SAM) affects 17 million children globally and is the most life-threatening form of malnutrition. Community-based management of acute malnutrition using ready-to-use therapeutic food (RUTF) has transformed outcomes for children with uncomplicated SAM, but those presenting with poor appetite or medical complications (categorised as having 'complicated' SAM) require hospitalisation. Data show that pneumonia, diarrhoea and malaria are leading causes of death in children with complicated SAM after discharge from hospital. High risk of infectious deaths suggests that sustained antimicrobial interventions may reduce mortality following discharge from hospital. Furthermore, children with complicated SAM respond less well to nutritional rehabilitation, and oftentimes are discharged to a home environment characterised by poverty and multiple caregiver vulnerabilities including depression, low decision making autonomy, lack of social support, gender-restricted family relations, and competing demands on scarce resources. Caregivers have to navigate diverse challenges that impede engagement with clinical care after discharge from hospital. The objective is to address the biological and social determinants of multimorbidity in children with complicated SAM by developing multimodal packages of interventions and testing them in a 5-arm adaptive randomized controlled clinical trial, with death/hospitalization or failed nutritional recovery as the primary outcome.
- Detailed Description
This is a 5-arm randomized, unblinded clinical trial comparing:
Arm 1: Standard-of-care (control) Arm 2: Antimicrobial package Arm 3: Reformulated RUTF Arm 4: Psychosocial package Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
The trial will test the superiority of each intervention arm over the standard of care arm (control). Children in the control arm (and all intervention arms) will receive RUTF for at least 2 weeks and all standard care. The trial is adaptive, meaning i) that each intervention arm will be added as it becomes available, and ii) an interim analysis will enable us to drop arms which are unpromising based on pre-specified criteria. There will be no blinding or placebo, because the very different components in each trial arm make it very challenging to blind. Children with complicated SAM will be screened and enrolled from hospital sites shortly before discharge, and interventions will be started before leaving hospital, and continued for 12 weeks through outpatient visits. Children will be followed at 2, 4, 6, 8, 12 and 24 weeks post-discharge in dedicated study clinics (with additional visits at 1, 3 and 5 weeks for caregiver-child pairs receiving the psychosocial intervention).
The primary outcome is death or hospitalization or failed nutritional recovery by 24 weeks.
The aim is to recruit 1266 children across three countries. The study is not testing new drugs but rather testing a different package of medications (Arms 2 and 5) as compared to current standard care, which the investigator believe will have greater benefit. The RUTF will be a new formula in two of the arms (3 and 5) based on research into what composition will improve health outcomes for children with complicated SAM. This will be a variant on Plumpy'NutĀ®, a brand that is known and trusted, produced in collaboration with the manufacturers, Nutriset.
The Psychosocial intervention (Arms 4 and 5) will involve three components:
i) The Friendship Bench, which was developed in Zimbabwe as a low-cost psychological intervention utilising problem-solving therapy (delivered by trained lay workers) and peer-to-peer support to address depression and other common mental disorders. There is a strong evidence-base for its use in urban LMIC settings. Peer support groups meet every 1-2 weeks and focus on communal problem solving, and establishing income-generation activities (such as making bags). ii) Care for Child Development is a UNICEF package that helps families build stronger relationships and solve problems in caring for the child at home, through play and communication activities to stimulate children, through a series of age-appropriate interactive modules delivered by a lay worker using 'flash' cards. It has been used in other African contexts and has good acceptability. iii) Educational and behavior-change messages around better nutrition; play for children with SAM; stigma, HIV and gender-based violence; financial planning; causes of SAM; and health-seeking behaviours.
Blood and stool will be collected at baseline, 12 and 24 weeks from all children to explore recovery of underlying pathological processes. At week 2, liver function tests will be undertaken in local laboratories. Samples will also be transported to Kenya and the Netherlands for some assays not available in each country.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1266
- Age 6-59 months, of either sex
- Hospitalised with complicated severe acute malnutrition, as per WHO definition
- Started transition to RUTF
- Caregiver willing and able to attend the study clinic for all visits
- Caregiver able and willing to give informed consent
- Any acute or chronic condition which mean that receipt of one or more study interventions, or participation in the trial, would not be advisable.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1: Standard-of-care (control) Standard Care Children in the control arm will receive Ready to Use Therapeutic Food (RUTF) for at least 2 weeks, plus all standard care. Children with HIV will receive long-term Cotrimoxazole prophylaxis and antiretroviral therapy, as per current guidelines. Arm 3: Reformulated RUTF Standard Care Children will receive a reformulated RUTF, with increased medium-chain triglycerides (MCTs), higher hydrolysed protein content and a more bioavailable form of selenium (selenium yeast). Children will receive RUTF for at least 2 weeks. Arm 2: Antimicrobial package Isoniazid Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks. Arm 2: Antimicrobial package Standard Care Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks. Arm 4: Psychosocial package The Friendship Bench Caregiver-child pairs will receive a low-cost, co-designed intervention to strengthen caregiver support, enhance income generation and promote child play. This is delivered over 12 weeks and comprises: i) The Friendship Bench, developed as a low-cost psychological intervention utilising problem-solving therapy (delivered by trained lay workers) and peer-to-peer support to address depression and other common mental disorders. ii) Care for Child Development is a UNICEF package that helps families build stronger relationships and solve problems in caring for the child at home, through play and communication activities in a series of age-appropriate interactive modules delivered by a lay worker using 'flash' cards. iii) Educational and behaviour-change messages around better nutrition; play for children with SAM; stigma, HIV and gender-based violence; financial planning; causes of SAM; and health-seeking behaviours. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package The Friendship Bench A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package Care for Child Development A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package Standard Care A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. Arm 3: Reformulated RUTF Reformulated Ready to Use Therapeutic Food Children will receive a reformulated RUTF, with increased medium-chain triglycerides (MCTs), higher hydrolysed protein content and a more bioavailable form of selenium (selenium yeast). Children will receive RUTF for at least 2 weeks. Arm 4: Psychosocial package Care for Child Development Caregiver-child pairs will receive a low-cost, co-designed intervention to strengthen caregiver support, enhance income generation and promote child play. This is delivered over 12 weeks and comprises: i) The Friendship Bench, developed as a low-cost psychological intervention utilising problem-solving therapy (delivered by trained lay workers) and peer-to-peer support to address depression and other common mental disorders. ii) Care for Child Development is a UNICEF package that helps families build stronger relationships and solve problems in caring for the child at home, through play and communication activities in a series of age-appropriate interactive modules delivered by a lay worker using 'flash' cards. iii) Educational and behaviour-change messages around better nutrition; play for children with SAM; stigma, HIV and gender-based violence; financial planning; causes of SAM; and health-seeking behaviours. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package Reformulated Ready to Use Therapeutic Food A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. Arm 4: Psychosocial package Standard Care Caregiver-child pairs will receive a low-cost, co-designed intervention to strengthen caregiver support, enhance income generation and promote child play. This is delivered over 12 weeks and comprises: i) The Friendship Bench, developed as a low-cost psychological intervention utilising problem-solving therapy (delivered by trained lay workers) and peer-to-peer support to address depression and other common mental disorders. ii) Care for Child Development is a UNICEF package that helps families build stronger relationships and solve problems in caring for the child at home, through play and communication activities in a series of age-appropriate interactive modules delivered by a lay worker using 'flash' cards. iii) Educational and behaviour-change messages around better nutrition; play for children with SAM; stigma, HIV and gender-based violence; financial planning; causes of SAM; and health-seeking behaviours. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package Educational and behaviour-change modules A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. Arm 4: Psychosocial package Educational and behaviour-change modules Caregiver-child pairs will receive a low-cost, co-designed intervention to strengthen caregiver support, enhance income generation and promote child play. This is delivered over 12 weeks and comprises: i) The Friendship Bench, developed as a low-cost psychological intervention utilising problem-solving therapy (delivered by trained lay workers) and peer-to-peer support to address depression and other common mental disorders. ii) Care for Child Development is a UNICEF package that helps families build stronger relationships and solve problems in caring for the child at home, through play and communication activities in a series of age-appropriate interactive modules delivered by a lay worker using 'flash' cards. iii) Educational and behaviour-change messages around better nutrition; play for children with SAM; stigma, HIV and gender-based violence; financial planning; causes of SAM; and health-seeking behaviours. Arm 2: Antimicrobial package Azithromycin Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks. Arm 2: Antimicrobial package Rifampicin Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks. Arm 2: Antimicrobial package Pyridoxine Hydrochloride Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package Azithromycin A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package Rifampicin A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package Isoniazid A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package Pyridoxine Hydrochloride A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks.
- Primary Outcome Measures
Name Time Method Death or first hospitalisation or failed nutritional recovery within 24 weeks post-randomisation 24 weeks post-randomisation a) All-cause mortality. b) Overnight admission to a health facility for any reason. This includes cases where there was a clinical plan to hospitalise the child, which was refused by the caregiver. c) Failed nutritional recovery is defined as either: i) Persistent WHZ\<-2 or MUAC\<12.5cm or bilateral pedal oedema at week 12; or ii) WHZ\<-2 or MUAC\<12.5cm or bilateral pedal oedema at any time between baseline and week 24 post-randomisation in a child who had previously recovered.
- Secondary Outcome Measures
Name Time Method Change in weight-for-age Z-score 24 weeks post-randomisation Change in weight-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards.
Number of participants with suspected or confirmed tuberculosis,pneumonia, diarrhoea or malaria 24 weeks post-randomisation Physician-diagnosed suspected or confirmed infection, as defined by WHO guidelines, between baseline and 24 weeks post-randomisation.
Change in mid-upper arm circumference 24 weeks post-randomisation Change in size of mid-upper arm in centimetres between baseline and 24 weeks.
Change in weight-for-height Z-score 24 weeks post-randomisation Change in weight-for-height Z-score between baseline and 24 weeks post-randomisation according to age- and-sex appropriate WHO reference standards.
Change in height-for-age Z-score 24 weeks post-randomisation Change in height-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards.
Trial Locations
- Locations (5)
Matero Hospital
šæš²Lusaka, Zambia
UTH - University Teaching Hospital
šæš²Lusaka, Zambia
Chitungwiza Central Hospital
šæš¼Harare, Zimbabwe
Parirenyatwa Hospital
šæš¼Harare, Zimbabwe
Sally Mugabe Hospital
šæš¼Harare, Zimbabwe