An Adaptive Multi-arm Trial to Improve Clinical Outcomes Among Children Recovering From Complicated SAM

Study Overview
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Brief Summary
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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
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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'Nut®, 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.

Official Title
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Co-SAM: An Adaptive Multi-arm Trial to Improve Clinical Outcomes Among Children Recovering From Complicated Severe Acute Malnutrition

Conditions
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Severe Acute Malnutrition, HIV, Comorbidities and Coexisting Conditions, Child Malnutrition

Intervention / Treatment
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* Drug: Rifampicin
* Drug: Azithromycin
* Drug: Isoniazid
* Drug: Pyridoxine Hydrochloride
* Behavioral: The Friendship Bench
* Behavioral: Care for Child Development
* Behavioral: Educational and behaviour-change modules
* Dietary Supplement: Reformulated Ready to Use Therapeutic Food
* Other: Standard Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: Any acute or chronic condition which mean that receipt of one or more study interventions, or participation in the trial, would not be advisable.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Adaptive, multi-arm randomised controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1: Standard-of-care (control)<br>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. | Other: Standard Care<br>* All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.<br>|
| Experimental: Arm 2: Antimicrobial package<br>Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks. | Drug: Rifampicin<br>* Rifampicin is commonly used in the first-line management of paediatric tuberculosis, and is approved by the FDA (ID: 2862628) and the EMA (EMA/31710/2020).<br>Drug: Azithromycin<br>* Azithromycin is a macrolide antibiotic, and is approved for use in children by the FDA (ID: 3263750) and EMA (EMA/2872/2021).<br>Drug: Isoniazid<br>* Isoniazid is an antibiotic commonly used in the firstline treatment of tuberculosis, and as tuberculosis prophylaxis.<br>Drug: Pyridoxine Hydrochloride<br>* Pyridoxine is a form of vitamin B6 used to prevent peripheral neuropathy among children receiving isoniazid.<br>Other: Standard Care<br>* All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.<br>|
| Experimental: Arm 3: Reformulated RUTF<br>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. | Dietary Supplement: Reformulated Ready to Use Therapeutic Food<br>* A reformulated product designed to improve outcomes for children who have severe acute malnutrition.<br>Other: Standard Care<br>* All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.<br>|
| Experimental: Arm 4: Psychosocial package<br>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. | Behavioral: The Friendship Bench<br>* The Friendship Bench was developed in Zimbabwe as a low-cost psychological intervention utilising problemsolving 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).<br>Behavioral: Care for Child Development<br>* 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.<br>Behavioral: Educational and behaviour-change modules<br>* 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. These have been developed with caregivers affected by SAM in a previous study, through a series of codesign workshops, ensuring these are contextually relevant.<br>Other: Standard Care<br>* All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.<br>|
| Experimental: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package<br>A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks. | Drug: Rifampicin<br>* Rifampicin is commonly used in the first-line management of paediatric tuberculosis, and is approved by the FDA (ID: 2862628) and the EMA (EMA/31710/2020).<br>Drug: Azithromycin<br>* Azithromycin is a macrolide antibiotic, and is approved for use in children by the FDA (ID: 3263750) and EMA (EMA/2872/2021).<br>Drug: Isoniazid<br>* Isoniazid is an antibiotic commonly used in the firstline treatment of tuberculosis, and as tuberculosis prophylaxis.<br>Drug: Pyridoxine Hydrochloride<br>* Pyridoxine is a form of vitamin B6 used to prevent peripheral neuropathy among children receiving isoniazid.<br>Behavioral: The Friendship Bench<br>* The Friendship Bench was developed in Zimbabwe as a low-cost psychological intervention utilising problemsolving 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).<br>Behavioral: Care for Child Development<br>* 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.<br>Behavioral: Educational and behaviour-change modules<br>* 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. These have been developed with caregivers affected by SAM in a previous study, through a series of codesign workshops, ensuring these are contextually relevant.<br>Dietary Supplement: Reformulated Ready to Use Therapeutic Food<br>* A reformulated product designed to improve outcomes for children who have severe acute malnutrition.<br>Other: Standard Care<br>* All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality. | All-cause mortality. | 24 weeks post-randomisation | 
| Readmission to hospital. | 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. | 24 weeks post-randomisation | 
| Failed nutritional recovery. | 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. | 24 weeks post-randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in weight-for-height Z-score | Change in weight-for-height Z-score between baseline and 24 weeks post-randomisation according to age- and-sex appropriate WHO reference standards. | 24 weeks post-randomisation | 
| Change in mid-upper arm circumference | Change in size of mid-upper arm in centimetres between baseline and 24 weeks. | 24 weeks post-randomisation | 
| Change in weight-for-age Z-score | Change in weight-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards. | 24 weeks post-randomisation | 
| Change in height-for-age Z-score | Change in height-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards. | 24 weeks post-randomisation | 
| Number of participants with suspected or confirmed tuberculosis,pneumonia, diarrhoea or malaria | Physician-diagnosed suspected or confirmed infection, as defined by WHO guidelines, between baseline and 24 weeks post-randomisation. | 24 weeks post-randomisation |