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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: HIV; Severe Acute Malnutrition; Comorbidities and Coexisting Conditions; Child Malnutrition
• Intervention / Treatment: Other: Standard Care; Drug: Rifampicin; Drug: Azithromycin; Drug: Isoniazid; Drug: Pyridoxine Hydrochloride; Dietary supplement: Reformulated Ready to Use Therapeutic Food; Behavioral: The Friendship Bench; Behavioral: Care for Child Development; Behavioral: Educational and behaviour-change modules

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'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.

• Study Type: Interventional
• Enrollment (Estimated): 1266
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Isabella Cordani, BSc; Phone Number: + 44 (0)2078822800; Email: i.cordani@qmul.ac.uk
• Study Contact Backup: Name: Andrew Prendergast, DPhil MRCPCH; Phone Number: +44 (0) 207 882 2269; Email: a.prendergast@qmul.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1: Standard-of-care (control); 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; All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.
Experimental: Arm 2: Antimicrobial package; Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks.	Other: Standard Care; All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.; Drug: Rifampicin; 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).; Drug: Azithromycin; Azithromycin is a macrolide antibiotic, and is approved for use in children by the FDA (ID: 3263750) and EMA (EMA/2872/2021).; Drug: Isoniazid; Isoniazid is an antibiotic commonly used in the firstline treatment of tuberculosis, and as tuberculosis prophylaxis.; Drug: Pyridoxine Hydrochloride; Pyridoxine is a form of vitamin B6 used to prevent peripheral neuropathy among children receiving isoniazid.
Experimental: Arm 3: Reformulated RUTF; 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.	Other: Standard Care; All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.; Dietary supplement: Reformulated Ready to Use Therapeutic Food; A reformulated product designed to improve outcomes for children who have severe acute malnutrition.
Experimental: Arm 4: Psychosocial package; 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.	Other: Standard Care; All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.; Behavioral: The Friendship Bench; 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).; Behavioral: Care for Child Development; 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.; Behavioral: Educational and behaviour-change modules; 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.
Experimental: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package; A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks.	Other: Standard Care; All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.; Drug: Rifampicin; 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).; Drug: Azithromycin; Azithromycin is a macrolide antibiotic, and is approved for use in children by the FDA (ID: 3263750) and EMA (EMA/2872/2021).; Drug: Isoniazid; Isoniazid is an antibiotic commonly used in the firstline treatment of tuberculosis, and as tuberculosis prophylaxis.; Drug: Pyridoxine Hydrochloride; Pyridoxine is a form of vitamin B6 used to prevent peripheral neuropathy among children receiving isoniazid.; Dietary supplement: Reformulated Ready to Use Therapeutic Food; A reformulated product designed to improve outcomes for children who have severe acute malnutrition.; Behavioral: The Friendship Bench; 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).; Behavioral: Care for Child Development; 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.; Behavioral: Educational and behaviour-change modules; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in anthropometry: Weight-for-height Z score (WHZ)	Change in WHZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.	4 weeks post-randomisation and 12 weeks post-randomisation
Change in anthropometry: Weight-for-age Z score (WAZ)	Change in WAZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.	4 weeks post-randomisation and 12 weeks post-randomisation
Change in anthropometry: Height-for-age Z score (HAZ)	Change in HAZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.	4 weeks post-randomisation and 12 weeks post-randomisation
Change in anthropometry: Mid-upper arm circumference (MUAC)	Change in MUAC between baseline and 12 weeks post-randomisation.	4 weeks post-randomisation and 12 weeks post-randomisation
Change in caregiver mental health	Change in Shona Symptom Questionnaire score (and proportion meeting cut-off score >8) between baseline and 24 weeks post-randomisation. This is a widely used 10-item self-report questionnaire. Each item is scored from 0-3, leading to a total score between 0-30, with higher scores indicating more severe depressive symptoms.	24 weeks post-randomisation
Concentration of lipid mediators/proteins	LC-MS measurement of fatty acids, acylcarnitines, polyamines, amino acids, glycolysis intermediates, TCA cycle intermediates, nucleotides, prostaglandins, serotonin, bile acids, lysophosphatidylcholines, phosphatidylcholines, cholesterol and derivatives, organic acids and tri/di/monoglycerides.	12 weeks and 24 weeks post-randomisation
Concentration of metabolites	Luminex measurement of Insulin, Insulin-like growth factor 1, leptin, ghrelin, cortisol, growth hormone, Glucagon-like peptide-1, Peptide YY, Monocyte chemoattractant protein-1, and Plasminogen activator inhibitor-1.	12 weeks and 24 weeks post-randomisation
Concentration of inflammatory mediators	Luminex measurement of chemokines, cytokines and circulating growth factors.	12 weeks and 24 weeks post-randomisation

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Collaborators: University of Washington; University of Oxford; KEMRI-Wellcome Trust Collaborative Research Program; Wageningen University; University of Cambridge; National Institute for Health Research, United Kingdom; Kenya Medical Research Institute; Tropical Gastroenterology & Nutrition Group (TROPGAN); Zvitambo Institute for Maternal & Child Health

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: July 14, 2023
• First Submitted That Met QC Criteria: August 8, 2023
• First Posted (Actual): August 16, 2023

Study Record Updates

• Last Update Posted (Actual): August 16, 2023
• Last Update Submitted That Met QC Criteria: August 8, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Malnutrition; Child Nutrition Disorders; Severe Acute Malnutrition; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Vitamins; Cytochrome P-450 CYP3A Inducers; Vitamin B Complex; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Rifampin; Azithromycin; Vitamin B 6; Pyridoxine; Isoniazid
• Other Study ID Numbers: 150522

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared at the end of the trial on ClinEpiDB.
• IPD Sharing Time Frame: January 2028
• IPD Sharing Access Criteria: Via ClinEpiDB
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No