xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05994742</url>
    </required_header>
    <id_info>
      <org_study_id>150522</org_study_id>
      <nct_id>NCT05994742</nct_id>
    </id_info>
    <brief_title>An Adaptive Multi-arm Trial to Improve Clinical Outcomes Among Children Recovering From Complicated SAM</brief_title>
    <acronym>Co-SAM</acronym>
    <official_title>Co-SAM: An Adaptive Multi-arm Trial to Improve Clinical Outcomes Among Children Recovering From Complicated Severe Acute Malnutrition</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Queen Mary University of London</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>University of Oxford</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>KEMRI-Wellcome Trust Collaborative Research Program</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>University of Washington</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Wageningen University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Zvitambo Institute for Maternal &amp; Child Health</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Tropical Gastroenterology &amp; Nutrition Group (TROPGAN)</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>University of Cambridge</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Kenya Medical Research Institute</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>National Institute for Health Research, United Kingdom</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Queen Mary University of London</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        Malnutrition underlies 45% of child deaths, and has far-reaching educational, economic and&#xD;
        health consequences. Severe acute malnutrition (SAM) affects 17 million children globally and&#xD;
        is the most life-threatening form of malnutrition. Community-based management of acute&#xD;
        malnutrition using ready-to-use therapeutic food (RUTF) has transformed outcomes for children&#xD;
        with uncomplicated SAM, but those presenting with poor appetite or medical complications&#xD;
        (categorised as having 'complicated' SAM) require hospitalisation. Data show that pneumonia,&#xD;
        diarrhoea and malaria are leading causes of death in children with complicated SAM after&#xD;
        discharge from hospital. High risk of infectious deaths suggests that sustained antimicrobial&#xD;
        interventions may reduce mortality following discharge from hospital. Furthermore, children&#xD;
        with complicated SAM respond less well to nutritional rehabilitation, and oftentimes are&#xD;
        discharged to a home environment characterised by poverty and multiple caregiver&#xD;
        vulnerabilities including depression, low decision making autonomy, lack of social support,&#xD;
        gender-restricted family relations, and competing demands on scarce resources. Caregivers&#xD;
        have to navigate diverse challenges that impede engagement with clinical care after discharge&#xD;
        from hospital. The objective is to address the biological and social determinants of&#xD;
        multimorbidity in children with complicated SAM by developing multimodal packages of&#xD;
        interventions and testing them in a 5-arm adaptive randomized controlled clinical trial, with&#xD;
        death/hospitalization or failed nutritional recovery as the primary outcome.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This is a 5-arm randomized, unblinded clinical trial comparing:&#xD;
  &#xD;
        Arm 1: Standard-of-care (control) Arm 2: Antimicrobial package Arm 3: Reformulated RUTF Arm&#xD;
        4: Psychosocial package Arm 5: Antimicrobial package + reformulated RUTF + psychosocial&#xD;
        package&#xD;
  &#xD;
        The trial will test the superiority of each intervention arm over the standard of care arm&#xD;
        (control). Children in the control arm (and all intervention arms) will receive RUTF for at&#xD;
        least 2 weeks and all standard care. The trial is adaptive, meaning i) that each intervention&#xD;
        arm will be added as it becomes available, and ii) an interim analysis will enable us to drop&#xD;
        arms which are unpromising based on pre-specified criteria. There will be no blinding or&#xD;
        placebo, because the very different components in each trial arm make it very challenging to&#xD;
        blind. Children with complicated SAM will be screened and enrolled from hospital sites&#xD;
        shortly before discharge, and interventions will be started before leaving hospital, and&#xD;
        continued for 12 weeks through outpatient visits. Children will be followed at 2, 4, 6, 8, 12&#xD;
        and 24 weeks post-discharge in dedicated study clinics (with additional visits at 1, 3 and 5&#xD;
        weeks for caregiver-child pairs receiving the psychosocial intervention).&#xD;
  &#xD;
        The primary outcome is death or hospitalization or failed nutritional recovery by 24 weeks.&#xD;
  &#xD;
        The aim is to recruit 1266 children across three countries. The study is not testing new&#xD;
        drugs but rather testing a different package of medications (Arms 2 and 5) as compared to&#xD;
        current standard care, which the investigator believe will have greater benefit. The RUTF&#xD;
        will be a new formula in two of the arms (3 and 5) based on research into what composition&#xD;
        will improve health outcomes for children with complicated SAM. This will be a variant on&#xD;
        Plumpy'Nut®, a brand that is known and trusted, produced in collaboration with the&#xD;
        manufacturers, Nutriset.&#xD;
  &#xD;
        The Psychosocial intervention (Arms 4 and 5) will involve three components:&#xD;
  &#xD;
        i) The Friendship Bench, which was developed in Zimbabwe as a low-cost psychological&#xD;
        intervention utilising problem-solving therapy (delivered by trained lay workers) and&#xD;
        peer-to-peer support to address depression and other common mental disorders. There is a&#xD;
        strong evidence-base for its use in urban LMIC settings. Peer support groups meet every 1-2&#xD;
        weeks and focus on communal problem solving, and establishing income-generation activities&#xD;
        (such as making bags). ii) Care for Child Development is a UNICEF package that helps families&#xD;
        build stronger relationships and solve problems in caring for the child at home, through play&#xD;
        and communication activities to stimulate children, through a series of age-appropriate&#xD;
        interactive modules delivered by a lay worker using 'flash' cards. It has been used in other&#xD;
        African contexts and has good acceptability. iii) Educational and behavior-change messages&#xD;
        around better nutrition; play for children with SAM; stigma, HIV and gender-based violence;&#xD;
        financial planning; causes of SAM; and health-seeking behaviours.&#xD;
  &#xD;
        Blood and stool will be collected at baseline, 12 and 24 weeks from all children to explore&#xD;
        recovery of underlying pathological processes. At week 2, liver function tests will be&#xD;
        undertaken in local laboratories. Samples will also be transported to Kenya and the&#xD;
        Netherlands for some assays not available in each country.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">March 1, 2024</start_date>
    <completion_date type="Anticipated">September 1, 2027</completion_date>
    <primary_completion_date type="Anticipated">March 1, 2026</primary_completion_date>
    <phase>Phase 3</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Adaptive, multi-arm randomised controlled trial</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Mortality.</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <description>All-cause mortality.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Readmission to hospital.</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <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.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Failed nutritional recovery.</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <description>Failed nutritional recovery is defined as either: i) Persistent WHZ&lt;-2 or MUAC&lt;12.5cm or bilateral pedal oedema at week 12; or ii) WHZ&lt;-2 or MUAC&lt;12.5cm or bilateral pedal oedema at any time between baseline and week 24 post-randomisation in a child who had previously recovered.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Change in weight-for-height Z-score</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <description>Change in weight-for-height Z-score between baseline and 24 weeks post-randomisation according to age- and-sex appropriate WHO reference standards.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in mid-upper arm circumference</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <description>Change in size of mid-upper arm in centimetres between baseline and 24 weeks.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in weight-for-age Z-score</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <description>Change in weight-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in height-for-age Z-score</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <description>Change in height-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Number of participants with suspected or confirmed tuberculosis,pneumonia, diarrhoea or malaria</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <description>Physician-diagnosed suspected or confirmed infection, as defined by WHO guidelines, between baseline and 24 weeks post-randomisation.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Change in anthropometry: Weight-for-height Z score (WHZ)</measure>
      <time_frame>4 weeks post-randomisation and 12 weeks post-randomisation</time_frame>
      <description>Change in WHZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in anthropometry: Weight-for-age Z score (WAZ)</measure>
      <time_frame>4 weeks post-randomisation and 12 weeks post-randomisation</time_frame>
      <description>Change in WAZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in anthropometry: Height-for-age Z score (HAZ)</measure>
      <time_frame>4 weeks post-randomisation and 12 weeks post-randomisation</time_frame>
      <description>Change in HAZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in anthropometry: Mid-upper arm circumference (MUAC)</measure>
      <time_frame>4 weeks post-randomisation and 12 weeks post-randomisation</time_frame>
      <description>Change in MUAC between baseline and 12 weeks post-randomisation.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in caregiver mental health</measure>
      <time_frame>24 weeks post-randomisation</time_frame>
      <description>Change in Shona Symptom Questionnaire score (and proportion meeting cut-off score &gt;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.</description>
    </other_outcome>
    <other_outcome>
      <measure>Concentration of lipid mediators/proteins</measure>
      <time_frame>12 weeks and 24 weeks post-randomisation</time_frame>
      <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.</description>
    </other_outcome>
    <other_outcome>
      <measure>Concentration of metabolites</measure>
      <time_frame>12 weeks and 24 weeks post-randomisation</time_frame>
      <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.</description>
    </other_outcome>
    <other_outcome>
      <measure>Concentration of inflammatory mediators</measure>
      <time_frame>12 weeks and 24 weeks post-randomisation</time_frame>
      <description>Luminex measurement of chemokines, cytokines and circulating growth factors.</description>
    </other_outcome>
    <number_of_arms>5</number_of_arms>
    <enrollment type="Anticipated">1266</enrollment>
    <condition>Severe Acute Malnutrition</condition>
    <condition>HIV</condition>
    <condition>Comorbidities and Coexisting Conditions</condition>
    <condition>Child Malnutrition</condition>
    <arm_group>
      <arm_group_label>Arm 1: Standard-of-care (control)</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm 2: Antimicrobial package</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm 3: Reformulated RUTF</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm 4: Psychosocial package</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <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:&#xD;
  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.&#xD;
  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.&#xD;
  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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Rifampicin</intervention_name>
      <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).</description>
      <arm_group_label>Arm 2: Antimicrobial package</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Azithromycin</intervention_name>
      <description>Azithromycin is a macrolide antibiotic, and is approved for use in children by the FDA (ID: 3263750) and EMA (EMA/2872/2021).</description>
      <arm_group_label>Arm 2: Antimicrobial package</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Isoniazid</intervention_name>
      <description>Isoniazid is an antibiotic commonly used in the firstline treatment of tuberculosis, and as tuberculosis prophylaxis.</description>
      <arm_group_label>Arm 2: Antimicrobial package</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Pyridoxine Hydrochloride</intervention_name>
      <description>Pyridoxine is a form of vitamin B6 used to prevent peripheral neuropathy among children receiving isoniazid.</description>
      <arm_group_label>Arm 2: Antimicrobial package</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Behavioral</intervention_type>
      <intervention_name>The Friendship Bench</intervention_name>
      <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).</description>
      <arm_group_label>Arm 4: Psychosocial package</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Behavioral</intervention_type>
      <intervention_name>Care for Child Development</intervention_name>
      <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.</description>
      <arm_group_label>Arm 4: Psychosocial package</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Behavioral</intervention_type>
      <intervention_name>Educational and behaviour-change modules</intervention_name>
      <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.</description>
      <arm_group_label>Arm 4: Psychosocial package</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Dietary Supplement</intervention_type>
      <intervention_name>Reformulated Ready to Use Therapeutic Food</intervention_name>
      <description>A reformulated product designed to improve outcomes for children who have severe acute malnutrition.</description>
      <arm_group_label>Arm 3: Reformulated RUTF</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Standard Care</intervention_name>
      <description>All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.</description>
      <arm_group_label>Arm 1: Standard-of-care (control)</arm_group_label>
      <arm_group_label>Arm 2: Antimicrobial package</arm_group_label>
      <arm_group_label>Arm 3: Reformulated RUTF</arm_group_label>
      <arm_group_label>Arm 4: Psychosocial package</arm_group_label>
      <arm_group_label>Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age 6-59 months, of either sex&#xD;
  &#xD;
            -  Hospitalised with complicated severe acute malnutrition, as per WHO definition&#xD;
  &#xD;
            -  Started transition to RUTF&#xD;
  &#xD;
            -  Caregiver willing and able to attend the study clinic for all visits&#xD;
  &#xD;
            -  Caregiver able and willing to give informed consent&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Any acute or chronic condition which mean that receipt of one or more study&#xD;
               interventions, or participation in the trial, would not be advisable.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>6 Months</minimum_age>
      <maximum_age>59 Months</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Isabella Cordani, BSc</last_name>
      <phone>+ 44 (0)2078822800</phone>
      <email>i.cordani@qmul.ac.uk</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Andrew Prendergast, DPhil MRCPCH</last_name>
      <phone>+44 (0) 207 882 2269</phone>
      <email>a.prendergast@qmul.ac.uk</email>
    </overall_contact_backup>
    <verification_date>June 2023</verification_date>
    <study_first_submitted>July 14, 2023</study_first_submitted>
    <study_first_submitted_qc>August 8, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 16, 2023</study_first_posted>
    <last_update_submitted>August 8, 2023</last_update_submitted>
    <last_update_submitted_qc>August 8, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 16, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Malnutrition</mesh_term>
      <mesh_term>Severe Acute Malnutrition</mesh_term>
      <mesh_term>Child Nutrition Disorders</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Pyridoxine</mesh_term>
      <mesh_term>Vitamin B 6</mesh_term>
      <mesh_term>Azithromycin</mesh_term>
      <mesh_term>Rifampin</mesh_term>
      <mesh_term>Isoniazid</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Data will be shared at the end of the trial on ClinEpiDB.</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
      <ipd_info_type>Analytic Code</ipd_info_type>
      <ipd_time_frame>January 2028</ipd_time_frame>
      <ipd_access_criteria>Via ClinEpiDB</ipd_access_criteria>
      <ipd_url>http://clinepidb.org</ipd_url>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05994742
  org study id: 150522
  nct id: NCT05994742
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  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.
  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.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Adaptive, multi-arm randomised controlled trial
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Mortality.
  time frame: 24 weeks post-randomisation
  description: All-cause mortality.
  measure: Readmission to hospital.
  time frame: 24 weeks post-randomisation
  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.
  measure: Failed nutritional recovery.
  time frame: 24 weeks post-randomisation
  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.
  measure: Change in weight-for-height Z-score
  time frame: 24 weeks post-randomisation
  description: Change in weight-for-height Z-score between baseline and 24 weeks post-randomisation according to age- and-sex appropriate WHO reference standards.
  measure: Change in mid-upper arm circumference
  time frame: 24 weeks post-randomisation
  description: Change in size of mid-upper arm in centimetres between baseline and 24 weeks.
  measure: Change in weight-for-age Z-score
  time frame: 24 weeks post-randomisation
  description: Change in weight-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards.
  measure: Change in height-for-age Z-score
  time frame: 24 weeks post-randomisation
  description: Change in height-for-age Z-score between baseline and 24 weeks post-randomisation according to age- and sex-appropriate WHO reference standards.
  measure: Number of participants with suspected or confirmed tuberculosis,pneumonia, diarrhoea or malaria
  time frame: 24 weeks post-randomisation
  description: Physician-diagnosed suspected or confirmed infection, as defined by WHO guidelines, between baseline and 24 weeks post-randomisation.
  measure: Change in anthropometry: Weight-for-height Z score (WHZ)
  time frame: 4 weeks post-randomisation and 12 weeks post-randomisation
  description: Change in WHZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.
  measure: Change in anthropometry: Weight-for-age Z score (WAZ)
  time frame: 4 weeks post-randomisation and 12 weeks post-randomisation
  description: Change in WAZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.
  measure: Change in anthropometry: Height-for-age Z score (HAZ)
  time frame: 4 weeks post-randomisation and 12 weeks post-randomisation
  description: Change in HAZ between baseline and 4 weeks post-randomisation, and baseline and 12 weeks post-randomisation.
  measure: Change in anthropometry: Mid-upper arm circumference (MUAC)
  time frame: 4 weeks post-randomisation and 12 weeks post-randomisation
  description: Change in MUAC between baseline and 12 weeks post-randomisation.
  measure: Change in caregiver mental health
  time frame: 24 weeks post-randomisation
  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.
  measure: Concentration of lipid mediators/proteins
  time frame: 12 weeks and 24 weeks post-randomisation
  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.
  measure: Concentration of metabolites
  time frame: 12 weeks and 24 weeks post-randomisation
  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.
  measure: Concentration of inflammatory mediators
  time frame: 12 weeks and 24 weeks post-randomisation
  description: Luminex measurement of chemokines, cytokines and circulating growth factors.
  arm group label: Arm 1: Standard-of-care (control)
  arm group type: Active Comparator
  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 group label: Arm 2: Antimicrobial package
  arm group type: Experimental
  description: Children will receive a bundle of azithromycin (3 days every month), isoniazid (daily), rifampicin (daily) and pyridoxine (daily) for 12 weeks.
  arm group label: Arm 3: Reformulated RUTF
  arm group type: Experimental
  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 group label: Arm 4: Psychosocial package
  arm group type: Experimental
  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 group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  arm group type: Experimental
  description: A combination of all interventions from arms 2, 3 and 4, plus standard care delivered for 12 weeks.
  intervention type: Drug
  intervention name: Rifampicin
  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).
  arm group label: Arm 2: Antimicrobial package
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  intervention type: Drug
  intervention name: Azithromycin
  description: Azithromycin is a macrolide antibiotic, and is approved for use in children by the FDA (ID: 3263750) and EMA (EMA/2872/2021).
  arm group label: Arm 2: Antimicrobial package
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  intervention type: Drug
  intervention name: Isoniazid
  description: Isoniazid is an antibiotic commonly used in the firstline treatment of tuberculosis, and as tuberculosis prophylaxis.
  arm group label: Arm 2: Antimicrobial package
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  intervention type: Drug
  intervention name: Pyridoxine Hydrochloride
  description: Pyridoxine is a form of vitamin B6 used to prevent peripheral neuropathy among children receiving isoniazid.
  arm group label: Arm 2: Antimicrobial package
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  intervention type: Behavioral
  intervention name: The Friendship Bench
  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).
  arm group label: Arm 4: Psychosocial package
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  intervention type: Behavioral
  intervention name: Care for Child Development
  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.
  arm group label: Arm 4: Psychosocial package
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  intervention type: Behavioral
  intervention name: Educational and behaviour-change modules
  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.
  arm group label: Arm 4: Psychosocial package
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  intervention type: Dietary Supplement
  intervention name: Reformulated Ready to Use Therapeutic Food
  description: A reformulated product designed to improve outcomes for children who have severe acute malnutrition.
  arm group label: Arm 3: Reformulated RUTF
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  intervention type: Other
  intervention name: Standard Care
  description: All children will receive care according to WHO guidelines, which includes standard RUTF and any other medications required.
  arm group label: Arm 1: Standard-of-care (control)
  arm group label: Arm 2: Antimicrobial package
  arm group label: Arm 3: Reformulated RUTF
  arm group label: Arm 4: Psychosocial package
  arm group label: Arm 5: Antimicrobial package + reformulated RUTF + psychosocial package
  criteria: 
  gender: All
  minimum age: 6 Months
  maximum age: 59 Months
  healthy volunteers: No
  last name: Isabella Cordani, BSc
  phone: + 44 (0)2078822800
  email: i.cordani@qmul.ac.uk
  last name: Andrew Prendergast, DPhil MRCPCH
  phone: +44 (0) 207 882 2269
  email: a.prendergast@qmul.ac.uk
  responsible party type: Sponsor
  mesh term: Malnutrition
  mesh term: Severe Acute Malnutrition
  mesh term: Child Nutrition Disorders
  mesh term: Pyridoxine
  mesh term: Vitamin B 6
  mesh term: Azithromycin
  mesh term: Rifampin
  mesh term: Isoniazid
  sharing ipd: Yes
  ipd description: Data will be shared at the end of the trial on ClinEpiDB.
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd info type: Informed Consent Form (ICF)
  ipd info type: Clinical Study Report (CSR)
  ipd info type: Analytic Code
  ipd time frame: January 2028
  ipd access criteria: Via ClinEpiDB
  ipd url: http://clinepidb.org