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

Primary Purpose

Severe Acute Malnutrition, HIV, Comorbidities and Coexisting Conditions

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Rifampicin
Azithromycin
Isoniazid
Pyridoxine Hydrochloride
The Friendship Bench
Care for Child Development
Educational and behaviour-change modules
Reformulated Ready to Use Therapeutic Food
Standard Care
Sponsored by
Queen Mary University of London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Acute Malnutrition

Eligibility Criteria

6 Months - 59 Months (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm 5

    Arm Type

    Active Comparator

    Experimental

    Experimental

    Experimental

    Experimental

    Arm Label

    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

    Arm Description

    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.

    Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks.

    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.

    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.

    A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks.

    Outcomes

    Primary Outcome Measures

    Mortality.
    All-cause mortality.
    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.
    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.

    Secondary Outcome Measures

    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.
    Change in mid-upper arm circumference
    Change in size of mid-upper arm in centimetres between baseline and 24 weeks.
    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.
    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.
    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.

    Full Information

    First Posted
    July 14, 2023
    Last Updated
    August 8, 2023
    Sponsor
    Queen Mary University of London
    Collaborators
    University of Oxford, KEMRI-Wellcome Trust Collaborative Research Program, University of Washington, Wageningen University, Zvitambo Institute for Maternal & Child Health, Tropical Gastroenterology & Nutrition Group (TROPGAN), University of Cambridge, Kenya Medical Research Institute, National Institute for Health Research, United Kingdom
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05994742
    Brief Title
    An Adaptive Multi-arm Trial to Improve Clinical Outcomes Among Children Recovering From Complicated SAM
    Acronym
    Co-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

    2. Study Status

    Record Verification Date
    June 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    March 1, 2024 (Anticipated)
    Primary Completion Date
    March 1, 2026 (Anticipated)
    Study Completion Date
    September 1, 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Queen Mary University of London
    Collaborators
    University of Oxford, KEMRI-Wellcome Trust Collaborative Research Program, University of Washington, Wageningen University, Zvitambo Institute for Maternal & Child Health, Tropical Gastroenterology & Nutrition Group (TROPGAN), University of Cambridge, Kenya Medical Research Institute, National Institute for Health Research, United Kingdom

    4. Oversight

    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
    Data Monitoring Committee
    Yes

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Severe Acute Malnutrition, HIV, Comorbidities and Coexisting Conditions, Child Malnutrition

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Model Description
    Adaptive, multi-arm randomised controlled trial
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    1266 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Arm 1: Standard-of-care (control)
    Arm Type
    Active Comparator
    Arm Description
    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 Title
    Arm 2: Antimicrobial package
    Arm Type
    Experimental
    Arm Description
    Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks.
    Arm Title
    Arm 3: Reformulated RUTF
    Arm Type
    Experimental
    Arm Description
    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 Title
    Arm 4: Psychosocial package
    Arm Type
    Experimental
    Arm Description
    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 Title
    Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
    Arm Type
    Experimental
    Arm Description
    A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    Rifampicin
    Intervention Description
    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).
    Intervention Type
    Drug
    Intervention Name(s)
    Azithromycin
    Intervention Description
    Azithromycin is a macrolide antibiotic, and is approved for use in children by the FDA (ID: 3263750) and EMA (EMA/2872/2021).
    Intervention Type
    Drug
    Intervention Name(s)
    Isoniazid
    Intervention Description
    Isoniazid is an antibiotic commonly used in the firstline treatment of tuberculosis, and as tuberculosis prophylaxis.
    Intervention Type
    Drug
    Intervention Name(s)
    Pyridoxine Hydrochloride
    Intervention Description
    Pyridoxine is a form of vitamin B6 used to prevent peripheral neuropathy among children receiving isoniazid.
    Intervention Type
    Behavioral
    Intervention Name(s)
    The Friendship Bench
    Intervention Description
    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).
    Intervention Type
    Behavioral
    Intervention Name(s)
    Care for Child Development
    Intervention Description
    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.
    Intervention Type
    Behavioral
    Intervention Name(s)
    Educational and behaviour-change modules
    Intervention Description
    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.
    Intervention Type
    Dietary Supplement
    Intervention Name(s)
    Reformulated Ready to Use Therapeutic Food
    Intervention Description
    A reformulated product designed to improve outcomes for children who have severe acute malnutrition.
    Intervention Type
    Other
    Intervention Name(s)
    Standard Care
    Intervention Description
    All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.
    Primary Outcome Measure Information:
    Title
    Mortality.
    Description
    All-cause mortality.
    Time Frame
    24 weeks post-randomisation
    Title
    Readmission to hospital.
    Description
    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.
    Time Frame
    24 weeks post-randomisation
    Title
    Failed nutritional recovery.
    Description
    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.
    Time Frame
    24 weeks post-randomisation
    Secondary Outcome Measure Information:
    Title
    Change in weight-for-height Z-score
    Description
    Change in weight-for-height Z-score between baseline and 24 weeks post-randomisation according to age- and-sex appropriate WHO reference standards.
    Time Frame
    24 weeks post-randomisation
    Title
    Change in mid-upper arm circumference
    Description
    Change in size of mid-upper arm in centimetres between baseline and 24 weeks.
    Time Frame
    24 weeks post-randomisation
    Title
    Change in weight-for-age Z-score
    Description
    Change in weight-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards.
    Time Frame
    24 weeks post-randomisation
    Title
    Change in height-for-age Z-score
    Description
    Change in height-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards.
    Time Frame
    24 weeks post-randomisation
    Title
    Number of participants with suspected or confirmed tuberculosis,pneumonia, diarrhoea or malaria
    Description
    Physician-diagnosed suspected or confirmed infection, as defined by WHO guidelines, between baseline and 24 weeks post-randomisation.
    Time Frame
    24 weeks post-randomisation
    Other Pre-specified Outcome Measures:
    Title
    Change in anthropometry: Weight-for-height Z score (WHZ)
    Description
    Change in WHZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.
    Time Frame
    4 weeks post-randomisation and 12 weeks post-randomisation
    Title
    Change in anthropometry: Weight-for-age Z score (WAZ)
    Description
    Change in WAZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.
    Time Frame
    4 weeks post-randomisation and 12 weeks post-randomisation
    Title
    Change in anthropometry: Height-for-age Z score (HAZ)
    Description
    Change in HAZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.
    Time Frame
    4 weeks post-randomisation and 12 weeks post-randomisation
    Title
    Change in anthropometry: Mid-upper arm circumference (MUAC)
    Description
    Change in MUAC between baseline and 12 weeks post-randomisation.
    Time Frame
    4 weeks post-randomisation and 12 weeks post-randomisation
    Title
    Change in caregiver mental health
    Description
    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.
    Time Frame
    24 weeks post-randomisation
    Title
    Concentration of lipid mediators/proteins
    Description
    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.
    Time Frame
    12 weeks and 24 weeks post-randomisation
    Title
    Concentration of metabolites
    Description
    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.
    Time Frame
    12 weeks and 24 weeks post-randomisation
    Title
    Concentration of inflammatory mediators
    Description
    Luminex measurement of chemokines, cytokines and circulating growth factors.
    Time Frame
    12 weeks and 24 weeks post-randomisation

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    6 Months
    Maximum Age & Unit of Time
    59 Months
    Accepts Healthy Volunteers
    No
    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.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Isabella Cordani, BSc
    Phone
    + 44 (0)2078822800
    Email
    i.cordani@qmul.ac.uk
    First Name & Middle Initial & Last Name or Official Title & Degree
    Andrew Prendergast, DPhil MRCPCH
    Phone
    +44 (0) 207 882 2269
    Email
    a.prendergast@qmul.ac.uk

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing 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 URL
    http://clinepidb.org

    Learn more about this trial

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

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