Clinical trial NCT05994742: An Adaptive Multi-arm Trial to Improve Clinical Outcomes Among Children Recovering From Complicated SAM
Official title: Co-SAM: An Adaptive Multi-arm Trial to Improve Clinical Outcomes Among Children Recovering From Complicated Severe Acute Malnutrition
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Severe Acute Malnutrition
HIV
Comorbidities and Coexisting Conditions
Child Malnutrition
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
Collaborators: name: University of Oxford
name: KEMRI-Wellcome Trust Collaborative Research Program
name: University of Washington
name: Wageningen University
name: Zvitambo Institute for Maternal & Child Health
name: Tropical Gastroenterology & Nutrition Group (TROPGAN)
name: University of Cambridge
name: Kenya Medical Research Institute
name: National Institute for Health Research, United Kingdom
First posted: 2023-08-16
Enrollment: 1266
Sex: ALL
Minimum age (years): 6
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Adaptive, multi-arm randomised controlled trial
Primary purpose: TREATMENT

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'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.

Eligibility criteria: 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.

Primary outcomes:
measure: Death or first hospitalisation or failed nutritional recovery within 24 weeks post-randomisation
timeFrame: 24 weeks post-randomisation
Secondary outcomes:
measure: Change in weight-for-height Z-score
timeFrame: 24 weeks post-randomisation
measure: Change in mid-upper arm circumference
timeFrame: 24 weeks post-randomisation
measure: Change in weight-for-age Z-score
timeFrame: 24 weeks post-randomisation
measure: Change in height-for-age Z-score
timeFrame: 24 weeks post-randomisation
measure: Number of participants with suspected or confirmed tuberculosis,pneumonia, diarrhoea or malaria
timeFrame: 24 weeks post-randomisation
Other outcomes:
measure: Change in anthropometry: Weight-for-height Z score (WHZ)
timeFrame: 4 weeks post-randomisation and 12 weeks post-randomisation
measure: Change in anthropometry: Weight-for-age Z score (WAZ)
timeFrame: 4 weeks post-randomisation and 12 weeks post-randomisation
measure: Change in anthropometry: Height-for-age Z score (HAZ)
timeFrame: 4 weeks post-randomisation and 12 weeks post-randomisation
measure: Change in anthropometry: Mid-upper arm circumference (MUAC)
timeFrame: 4 weeks post-randomisation and 12 weeks post-randomisation
measure: Change in caregiver mental health
timeFrame: 24 weeks post-randomisation
measure: Concentration of lipid mediators/proteins
timeFrame: 12 weeks and 24 weeks post-randomisation
measure: Concentration of metabolites
timeFrame: 12 weeks and 24 weeks post-randomisation
measure: Concentration of inflammatory mediators
timeFrame: 12 weeks and 24 weeks post-randomisation
Locations:
city: Lusaka
country: Zambia
facility: Matero Hospital
city: Lusaka
country: Zambia
facility: UTH - University Teaching Hospital
city: Harare
country: Zimbabwe
facility: Chitungwiza Central Hospital
city: Harare
country: Zimbabwe
facility: Parirenyatwa Hospital
city: Harare
country: Zimbabwe
facility: Sally Mugabe Hospital
Study officials:
References: