Trial no.:	PACTR202311478928378	Date of Approval:	06/11/2023
Trial Status:	Registered in accordance with WHO and ICMJE standards

TRIAL DESCRIPTION

Public title

CoSAM Trial

Official scientific title

An adaptive multi-arm trial to improve clinical outcomes among children recovering from complicated severe acute malnutrition

Brief summary describing the background and objectives of the trial

The background and objectives of this trial revolve around addressing the critical need for new interventions to improve the survival, health, growth, and development of children with Severe Acute Malnutrition (SAM). SAM is a major contributor to child mortality, with profound social, economic, and health implications. The trial aims to test various interventions to enhance the convalescence of children following hospital treatment for SAM, with the primary objective being to reduce the composite outcome of death, hospitalization, or failed nutritional recovery within 24 weeks after discharge. The trial is based on the principles that biological and social factors interact to drive multimorbidity in children with SAM, and that combined biomedical and psychosocial interventions can ameliorate these factors to reduce morbidity, mortality, and improve growth and neurodevelopment. It highlights the lack of evidence-based interventions for complicated SAM since WHO guidelines were released in 2000 and the need for more comprehensive approaches to convalescence. The trial will test three 'packages' of interventions against a common control arm receiving enhanced standard-of-care. These interventions are as follows: Standard-of-care (control): Based on WHO guidelines, including RUTF, HIV staging and treatment, and necessary medications. Antimicrobial package: A bundle of antibacterial and anti-TB therapy provided for 12 weeks post-discharge to prevent and treat infections. Reformulated RUTF: A modified version of Ready-to-Use Therapeutic Food (RUTF) designed to reduce metabolic stress and inflammation and enhance nutrient bioavailability. Psychosocial package: A low-cost, co-designed intervention to provide caregiver support, enhance income generation, and promote child play to improve convalescence and neurodevelopment. Combined package: Combines the antimicrobial package, reformulated RUTF, and psychosocial package. The trial will use an efficient adaptive design

Type of trial

RCT

Acronym (If the trial has an acronym then please provide)

III

Disease(s) or condition(s) being studied

Infections and Infestations,Neonatal Diseases,Nutritional, Metabolic, Endocrine

Sub-Disease(s) or condition(s) being studied

HIV/AIDS

Purpose of the trial

It seeks to improve the holistic well-being of children who have experienced severe malnutrition and the associated risks and challenges.

Anticipated trial start date

01/01/2024

Actual trial start date

15/07/2024

Anticipated date of last follow up

15/07/2026

Actual Last follow-up date

Anticipated target sample size (number of participants)

422

Actual target sample size (number of participants)

Recruitment status

Recruiting

Publication URL

Secondary Ids	Issuing authority/Trial register
	EDGE Number 150522

STUDY DESIGN
Intervention assignment	Allocation to intervention	If randomised, describe how the allocation sequence was generated	Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms	Masking	If masking / blinding was used
Parallel: different groups receive different interventions at same time during study	Randomised	Simple randomization using a randomization table created by a computer software program	Central randomisation by phone/fax	Open-label(Masking Not Used)

INTERVENTIONS
Intervention type	Intervention name	Dose	Duration	Intervention description	Group size	Nature of control
Control Group	Arm 1	The control group in this clinical trial (Arm 1: Standard-of-Care) receives the standard treatment protocol that serves as the reference point for evaluating the effectiveness of the experimental interventions. Specifically, participants in the control group receive the following interventions and care: Ready-to-Use Therapeutic Food (RUTF): Participants in the control group are provided with RUTF, a specialized, nutrient-dense food designed for the treatment of severe acute malnutrition. They will receive RUTF until they achieve nutritional recovery. Standard Care According to WHO Guidelines: In addition to RUTF, participants in the control group receive all standard care measures outlined in the World Health Organization (WHO) guidelines for the treatment of severe acute malnutrition. These guidelines encompass a range of medical, nutritional, and supportive measures to promote recovery and well-being. The purpose of the control group is to establish a baseline against which the effectiveness of the experimental intervention arms (Arms 2, 3, 4, and 5) can be compared. By providing the standard-of-care treatment, researchers can assess whether any of the experimental interventions offer superior outcomes in terms of the primary outcome, which is a composite measure of death, hospitalization, or failed nutritional recovery by 24 weeks post-randomization. This control group will help us determine if the new interventions are more effective than the existing standard of care for severe acute malnutrition.	12 weeks post-randomization	The control group in this clinical trial, known as Arm 1, will receive the standard-of-care treatment for severe acute malnutrition (SAM). The intervention for the control group is as follows: Control Group (Arm 1: Standard-of-Care): Ready-to-Use Therapeutic Food (RUTF): Participants in the control group receive RUTF, which is a specialized, nutrient-dense food designed for the treatment of severe acute malnutrition. They are provided with RUTF until they achieve nutritional recovery. Standard Care According to WHO Guidelines: In addition to RUTF, participants in the control group receive all standard care measures outlined in the World Health Organization (WHO) guidelines for the treatment of severe acute malnutrition. These guidelines encompass a range of medical, nutritional, and supportive measures to promote recovery and well-being. The specific details of standard care will include medical assessments, hydration management, and monitoring for any complications associated with severe malnutrition.	142	Active-Treatment of Control Group
Experimental Group	Arm 2	In Arm 2 of this clinical trial, participants receive an antimicrobial prophylaxis package consisting of azithromycin, isoniazid, and rifampicin for a duration of 12 weeks post-discharge. This intervention aims to prevent and treat intercurrent infections in children recovering from complicated severe acute malnutrition (SAM), with a focus on reducing the risk of death, hospitalization, or failed nutritional recovery. Azithromycin, a broad-spectrum antibiotic with immunomodulatory properties, is administered to clear subclinical infections and create a pathogen-free environment. Isoniazid is used for tuberculosis prevention, especially in high-risk cases, while rifampicin provides additional antibacterial coverage. The extended duration of antimicrobial therapy seeks to safeguard against infections during the vulnerable period following hospital discharge. This intervention is based on previous research, acknowledging the increased infection susceptibility of malnourished children, but also considers potential concerns related to drug resistance and cost-effectiveness in its evaluation to inform public health decision-making.	The duration of the antimicrobial prophylaxis intervention in Arm 2 of the clinical trial is 12 weeks post-discharge.	The antimicrobial prophylaxis intervention in Arm 2 of the clinical trial entails providing children recovering from complicated severe acute malnutrition (SAM) with a 12-week course of medications, including azithromycin, isoniazid, and rifampicin post-discharge. Azithromycin serves to clear subclinical infections, create a pathogen-free environment, and potentially mitigate the acute phase response, given its broad-spectrum antibiotic properties and immunomodulatory effects. Isoniazid is administered for tuberculosis prevention, especially in high-risk cases, while rifampicin offers additional antibacterial coverage and effectively treats small intestinal bacterial overgrowth. The intervention aims to reduce the risk of mortality, hospitalization, or failed nutritional recovery during the vulnerable post-discharge period. It is based on prior research indicating potential benefits but takes into account concerns regarding drug resistance and cost-effectiveness, which will be evaluated to inform public health decisions.	70
Experimental Group	Arm 3	In Arm 3 of the clinical trial, children admitted with complicated severe acute malnutrition (SAM) who have transitioned from therapeutic milk feeds to Ready-to-Use Therapeutic Food (RUTF) will receive a variable duration of RUTF supplementation based on their individual response to treatment. Initially, RUTF will be provided for at least 2 weeks, with the supply continuing beyond this period if necessary. The intervention aims to support the child until they achieve nutritional recovery, characterized by specific criteria such as a weight-for-height Z-score >-2, mid-upper arm circumference (MUAC) >12.5cm, and the absence of edema since the last study visit. If a child has not met these criteria by week 12, they will be classified as having reached the primary outcome of "failed nutritional recovery," and RUTF will be continued for a maximum of 16 weeks. In cases of relapse after nutritional recovery, RUTF supplementation will be restarted. This flexible dosing approach ensures that each child's nutritional needs are addressed until they reach the defined recovery criteria.	In Arm 3 of the clinical trial, the duration of Ready-to-Use Therapeutic Food (RUTF) supplementation can vary based on the individual response of each child. Initially, RUTF will be supplied for at least 2 weeks. However, the duration may extend beyond these initial 2 weeks, and the intervention will continue until the child achieves nutritional recovery. Nutritional recovery is defined as meeting specific criteria, including a weight-for-height Z-score >-2, mid-upper arm circumference (MUAC) >12.5cm, and being free of edema since the last study visit. If a child has not reached the criteria for nutritional recovery by week 12, they will be classified as having reached the primary outcome of "failed nutritional recovery," and RUTF will be continued for a maximum of 16 weeks. The duration of RUTF supplementation is therefore flexible and aims to support each child until they achieve and maintain nutritional recovery or address cases of relapse.	In Arm 3 of the clinical trial, children recovering from complicated severe acute malnutrition (SAM) receive a specialized intervention known as Ready-to-Use Therapeutic Food (RUTF). The distinguishing feature of this arm is the use of a reformulated RUTF, which may have altered nutrient composition but is not expected to compromise safety. While specific dosing details are not provided, RUTF is supplied for at least 2 weeks initially, with the intervention duration varying based on individual response. The primary goal is to support these children until they achieve nutritional recovery, defined by specific criteria, while considering the unique metabolic conditions in SAM. This intervention seeks to address the nutritional needs of participants and enhance their recovery during the trial.	70
Experimental Group	Arm 4	In Arm 4, which involves the psychosocial intervention, caregiver-child pairs receive weekly intervention visits at weeks 1, 3, and 5. These visits are designed to deliver weekly problem-solving therapy and behavior-change modules for a total duration of 6 weeks. The content and focus of these psychosocial sessions aim to support the psychosocial well-being of the participants.	The total duration of all interventions in Arm 4, as well as in other arms, is 12 weeks.	Specifically, caregiver-child pairs receive weekly intervention visits at weeks 1, 3, and 5. These visits are designed to deliver problem-solving therapy and behavior-change modules over this 6-week period to support the psychosocial well-being of the participants. It's important to note that this is the duration of the psychosocial component of the intervention within Arm 4. Additionally, there are standard intervention visits for all arms at weeks 2, 4, 6, 8, and 12 post-randomization, which include other aspects of the intervention such as the resupply of Ready-to-Use Therapeutic Food (RUTF)	70
Experimental Group	Arm 5	According to intervention Arm	The total intervention duration for all arms is 12 weeks.	In the combined arm, Arm 5, all of the interventions from Arms 2 (Antimicrobial package), 3 (Reformulated RUTF), and 4 (Psychosocial package) are given together. This means that participants in the combined arm receive a combination of the antimicrobial package, the reformulated RUTF, and the psychosocial intervention as part of their treatment. The combined arm is designed to assess the impact of these three interventions when administered together and evaluate whether the combination is more effective than the standard of care. The dosing and frequency of these interventions are typically specified in the trial protocol or related documents.	70

ELIGIBILITY CRITERIA
List inclusion criteria	List exclusion criteria	Age Category	Minimum age	Maximum age	Gender
1. Age 6-59 months, of either sex 2. Hospitalised with complicated severe acute malnutrition, as per WHO definitiona 3. Started transition from therapeutic milk feeds to RUTF 4. Caregiver willing and able to attend the study clinic for all visits 5. Caregiver able and willing to give informed consent	1. Any acute or chronic condition which mean that receipt of one or more study interventions, or participation in the trial, would not be advisable	Infant: 0 Month(s)-12 Month(s),Infant: 13 Month(s)-24 Month(s),New born: 0 Day-1 Month,Preschool Child: 2 Year-5 Year	6 Month(s)	59 Month(s)	Both

ETHICS APPROVAL

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

14/09/2023

UNIVERSITY OF ZAMBIA BIOMEDICAL RESEARCH ETHICS COMMITTEE

Ethics Committee Address
Street address	City	Postal code	Country
Nationalist Road, Lusaka	Lusaka	10101	Zambia

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

24/10/2023

KENYA MEDICAL RESEARCH INSTITUTE

Ethics Committee Address
Street address	City	Postal code	Country
OFF MBAGATHI ROAD	Nairobi	54840-002	Kenya

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

22/08/2023

Medical Research Council of Zimbabwe

Ethics Committee Address
Street address	City	Postal code	Country
20 Cambridge Road	Harare	A178	Zimbabwe

OUTCOMES
Type of outcome	Outcome	Timepoint(s) at which outcome measured
Primary Outcome	A composite of death or hospitalisation or failed nutritional recovery	By 24 weeks post-randomisation
Secondary Outcome	• Change in weight-for-height Z-score between baseline and 24 weeks postrandomisation • Change in mid-upper arm circumference between baseline and 24 weeks postrandomisation • Change in weight-for-age Z-score between baseline and 24 weeks postrandomisation • Change in height-for-age Z-score between baseline and 24 weeks postrandomisation • Suspected or confirmed tuberculosis, pneumonia, diarrhoea, or malaria through 24 weeks post-randomisation	24 weeks postrandomisation

RECRUITMENT CENTRES
Name of recruitment centre	Street address	City	Postal code	Country
University Teaching Hospital Childrens Hospital	Nationalist Road	Lusaka	10101	Zambia
Matero Level 1 Hospital	Matero	Lusaka	10101	Zambia
Migori referral hospital	Western Kenya	Western Kenya		Kenya
Homa Bay County referral hospital	Western Kenya	Western Kenya		Kenya
Mbagathi Hospital	Nairobi	Nairobi		Kenya
Coast General Hospital	Mombasa	Mombasa		Kenya
Sally Mugabe Hospital	Harare	Harare		Zimbabwe
Parirenyatwa Hospital	Harare	Harare		Zimbabwe
Chitungwiza Central Hospital	Batanai	Chitungwiza		Zimbabwe

FUNDING SOURCES
Name of source	Street address	City	Postal code	Country
National Institute for Health and Care Research	Central Commissioning Facility Grange House 15 Church Street Twickenham TW1 3NL, UK	Twickenham	TW1 3NL	United Kingdom

SPONSORS
Sponsor level	Name	Street address	City	Postal code	Country	Nature of sponsor
Primary Sponsor	Queen Mary University of London	Centre for Genomics and Child Health Blizard Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London 4 Newark St	London	London E1	United Kingdom	University

COLLABORATORS
Name	Street address	City	Postal code	Country

CONTACT PEOPLE
Role	Name	Email	Phone	Street address
Principal Investigator	Beatrice Chifwelu Amadi	beatriceamadi@ymail.com	+260966752739	24 Esther Lungu Road, Kamwala South
City	Postal code	Country	Position/Affiliation
Lusaka	10101	Zambia	Principal Investigator PI at TROPGAN
Role	Name	Email	Phone	Street address
Public Enquiries	Aaron Konzani Tembo	aaron@tropgan.net	+260962161076	24 Esther Lungu Road, Kamwala South
City	Postal code	Country	Position/Affiliation
Lusaka	10101	Zambia	Clinical Research and Compliance Manager at TROPGAN
Role	Name	Email	Phone	Street address
Scientific Enquiries	Paul Maurice Kelly	m.p.kelly@qmul.ac.uk	+260966751875	24 Esther Lungu Road, Kamwala South
City	Postal code	Country	Position/Affiliation
Lusaka	10101	Zambia	Principal Investigator PI at TROPGAN
Role	Name	Email	Phone	Street address
Principal Investigator	Benson Singa	singabo2008@gmail.com	+254725234844	00200 Off Raila Odinga Way
City	Postal code	Country	Position/Affiliation
Nairobi		Kenya	Kenyan Principal Investigator
Role	Name	Email	Phone	Street address
Principal Investigator	Mutsa Bwakura Dangarembizi	mbwakura@uz-ctrc.org	+263772601735	Mount Pleasant Drive
City	Postal code	Country	Position/Affiliation
Harare		Zimbabwe	Zimbabwean PI

REPORTING
Share IPD	Description	Additional Document Types	Sharing Time Frame	Key Access Criteria
Yes	The Individual Participant Data (IPD) Sharing Statement for this trial governs the sharing of data collected on individual participants during the study. IPD access will primarily be granted to the Chief Investigator (CI) and the trial statisticians who require this data for analysis. Formal requests for sharing IPD with parties beyond the CI and statisticians will be considered, but they must undergo a review process involving the Trial Management Group (TMG), Trial Steering Committee (TSC), and the sponsor. This ensures that access to sensitive participant data is carefully controlled and follows ethical and regulatory standards. Data privacy and security will be maintained at all times to protect the identity of participants. While trial results will be published openly, these publications will not include individual participant data. Regulatory authorities and authorized representatives will have access to the data when required for study-related monitoring and auditing. The sponsor is designated as the data controller, while the CI serves as the data custodian for all study-generated data. This structure underscores the commitment to safeguarding participant information and controlling access to individual participant data.	Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol	Within one year of the End of the Trial definition being reached.	Below is a description of Key Access Criteria for the Co-SAM trial: Access Criteria: • Access Type: Controlled Who May Request Access: • Authorized Users: The trial data access is primarily restricted to authorized users, which includes members of the research team and individuals or entities with legitimate reasons for accessing the data. Types of Data Analysis Permitted: •Types of Analysis: Data analysis related to the trial's objectives and research questions will be allowed. Process for Requesting Data/Documents: • Formal Request: Individuals or entities interested in accessing the trial data will need to submit a formal request. • Review and Approval: Once a request is submitted, it will be reviewed by relevant committees or authorities within the trial management structure. Who Will Decide (Third Party): • Review Committees: The decision regarding data access requests will be the responsibility of review committees within the Co-SAM trial structure. These committees will include the Trial Management Group (TMG), the Trial Steering Committee (TSC), and the Sponsor. • CI and Trial Statisticians: The Chief Investigator (CI) and trial statisticians are individuals who have access to the full dataset. They will also play a role in deciding on data access requests. Criteria for Reviewing Requests: • Based on considerations such as the requester's qualifications, the scientific merit of the proposed analysis, potential risks to participant confidentiality, and alignment with the trial's objectives.
URL	Results Available	Results Summary	Result Posting Date	First Journal Publication Date
	No
Result Upload 1:	Result Upload 2:	Result Upload 3:	Result Upload 4:	Result Upload 5:

Result URL Hyperlinks	Link To Protocol
Result URL Hyperlinks

Changes to trial information

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