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TAME trial: a multi-arm phase II randomised trial of four novel interventions for malnutrition enteropathy in Zambia and Zimbabwe - a study protocol.

ABSTRACT: INTRODUCTION:Severe acute malnutrition (SAM) in children in many countries still carries unacceptably high mortality, especially when complicated by secondary infection or metabolic derangements. New therapies are urgently needed and we have identified mucosal healing in the intestine as a potential target for novel treatment approaches. METHODS AND ANALYSIS:The TAME trial (Therapeutic Approaches for Malnutrition Enteropathy) will evaluate four novel treatments in an efficient multi-arm single-blind phase II design. In three hospitals in Zambia and Zimbabwe, 225 children with SAM will be randomised to one of these treatments or to standard care, once their inpatient treatment has reached the point of transition from stabilisation to increased nutritional intake. The four interventions are budesonide, bovine colostrum or N-acetyl glucosamine given orally or via nasogastric tube, or teduglutide given by subcutaneous injection. The primary endpoint will be a composite score of faecal inflammatory markers, and a range of secondary endpoints include clinical and laboratory endpoints. Treatments will be given daily for 14 days, and evaluation of the major endpoints will be at 14 to 18 days, with a final clinical evaluation at 28 days. In a subset of children in Zambia, endoscopic biopsies will be used to evaluate the effect of interventions in detail. ETHICS AND DISSEMINATION:The study has been approved by the University of Zambia Biomedical Research Ethics Committee (006-09-17, dated 9th July, 2018), and the Joint Research Ethics Committee of the University of Zimbabwe (24th July, 2019). Caregivers will provide written informed consent for each participant. Findings will be disseminated through peer-reviewed journals, conference presentations and to caregivers at face-to-face meetings. TRIAL REGISTRATION NUMBER:NCT03716115; Pre-results.

SUBMITTER: Kelly P

PROVIDER: S-EPMC6887014 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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TAME trial: a multi-arm phase II randomised trial of four novel interventions for malnutrition enteropathy in Zambia and Zimbabwe - a study protocol.

Kelly Paul P Bell Lauren L Amadi Beatrice B Bwakura-Dangarembizi Mutsa M VanBuskirk Kelley K Chandwe Kanta K Chipunza Miyoba M Ngosa Deophine D Chulu Nivea N Hill Susan S Murch Simon S Playford Raymond R Prendergast Andrew A

BMJ open 20191114 11

<h4>Introduction</h4>Severe acute malnutrition (SAM) in children in many countries still carries unacceptably high mortality, especially when complicated by secondary infection or metabolic derangements. New therapies are urgently needed and we have identified mucosal healing in the intestine as a potential target for novel treatment approaches.<h4>Methods and analysis</h4>The TAME trial (Therapeutic Approaches for Malnutrition Enteropathy) will evaluate four novel treatments in an efficient mul ...[more]

PMID: 31727642

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Project description:BackgroundChildren discharged from hospital following management of complicated severe acute malnutrition (SAM) have a high risk of mortality, especially HIV-positive children. Few studies have examined mortality in the antiretroviral therapy (ART) era.ObjectivesOur objectives were to ascertain 52-wk mortality in children discharged from hospital for management of complicated SAM, and to identify independent predictors of mortality.MethodsA prospective cohort study was conducted in children enrolled from 3 hospitals in Zambia and Zimbabwe between July 2016 and March 2018. The primary outcome was mortality at 52 wk. Univariable and multivariable Cox regression models were used to identify independent risk factors for death, and to investigate whether HIV modifies these associations.ResultsOf 745 children, median age at enrolment was 17.4 mo (IQR: 12.8, 22.1 mo), 21.7% were HIV-positive, and 64.4% had edema. Seventy children (9.4%; 95% CI: 7.4, 11.7%) died and 26 exited during hospitalization; 649 were followed postdischarge. At discharge, 43.9% had ongoing SAM and only 50.8% of HIV-positive children were receiving ART. Vital status was ascertained for 604 (93.1%), of whom 55 (9.1%; 95% CI: 6.9, 11.7%) died at median 16.6 wk (IQR: 9.4, 21.9 wk). Overall, 20.0% (95% CI: 13.5, 27.9%) and 5.6% (95% CI: 3.8, 7.9%) of HIV-positive and HIV-negative children, respectively, died [adjusted hazard ratio (aHR): 3.83; 95% CI: 2.15, 6.82]. Additional independent risk factors for mortality were ongoing SAM (aHR: 2.28; 95% CI: 1.22, 4.25), cerebral palsy (aHR: 5.60; 95% CI: 2.72, 11.50) and nonedematous SAM (aHR: 2.23; 95% CI: 1.24, 4.01), with no evidence of interaction with HIV status.ConclusionsHIV-positive children have an almost 4-fold higher mortality than HIV-negative children in the year following hospitalization for complicated SAM. A better understanding of causes of death, an improved continuum of care for HIV and SAM, and targeted interventions to improve convalescence are needed.

Project description:BackgroundCommunity-based programmes are a critical platform for improving child health and development. We tested the impact of a community-based early childhood intervention package in rural Zambia.MethodsWe conducted a non-blinded cluster randomised controlled trial in Southern Province, Zambia. 30 clusters of villages were matched based on population density and distance from the nearest health centre, and randomly assigned to intervention (15 clusters and 268 caregiver-child dyads) or control (15 clusters and 258 caregiver-child dyads). Caregivers were eligible if they had a child aged 6-12 months at baseline. In intervention clusters, health workers screened children for infections and malnutrition, and invited caregivers to attend fortnightly group meetings covering a nutrition and child development curriculum. 220 intervention and 215 control dyads were evaluated after 1 year. The primary outcomes were stunting and INTERGROWTH-21st neurodevelopmental assessment (NDA) scores. Weight-for-age and height-for-age z-scores based on WHO growth standards were also analysed. Secondary outcomes were child illness symptoms, dietary intake and caregiver-child interactions based on self-report. Impact was estimated using intention-to-treat analysis.ResultsThe intervention package was associated with a 0.12 SD increase in weight-for-age (95% CI -0.14 to 0.38), a 0.15 SD increase in height-for-age (95% CI -0.18 to 0.48) and a reduction in stunting (OR 0.68; 95% CI 0.36 to 1.28), whereas there was no measurable impact on NDA score. Children receiving the intervention package had fewer symptoms, a more diverse diet and more caregiver interactions.ConclusionsIn settings like Zambia, community-based early childhood programmes appear to be feasible and appreciated by caregivers, as evidenced by high rates of uptake. The intervention package improved parenting behaviours and had a small positive, though statistically insignificant, impact on child development. Given the short time frame of the project, larger developmental impact is likely if differential parenting behaviours persist.Trial registration numberNCT02234726; Results.

Project description:BackgroundChildhood stunting remains common in many low-income settings and is associated with increased morbidity and mortality, as well as impaired child development.MethodsThe main objective of the study was to assess whether home-installed growth charts as well as small-quantity lipid-based nutrient supplements (SQ-LNS) can reduce growth faltering among infants. All caregivers of infants between 2 and 10 months of age at baseline, and at least 6 months old at the beginning of the interventions, in 282 randomly selected enumeration areas in Choma, Mansa and Lusaka districts in Zambia were invited to participate in the study. Cluster randomisation was stratified by district. A software-generated random number draw was used to assign clusters to one of four arms: (1) no intervention (control); (2) home installation of a wall chart that contained a growth monitoring tool along with key messages on infant and young child feeding and nutrition (growth charts only); (3) 30 sachets of SQ-LNS delivered each month (SQ-LNS only) or (4) growth charts+SQ LNS. The primary outcomes were children's height-for-age z-score (HAZ) and stunting (HAZ <-2) after 18 months of intervention. Secondary outcomes were haemoglobin (Hb), anaemia (Hb<110.0 g/L), weight-for-height, weight-for-age z-score (WAZ), underweight (WAZ<-2) and child development measured by the Global Scales of Early Development (GSED). Outcomes were analysed intention to treat using adjusted linear and logistic regression models and compared each of the three interventions to the control group. Assessors and analysts were blinded to the treatment-blinding of participating families was not possible.ResultsA total of 2291 caregiver-child dyads across the 282 study clusters were included in the study. 70 clusters (557 dyads) were assigned to the control group, 70 clusters (643 dyads) to growth charts only, 71 clusters (525 dyads) to SQ-LNS and 71 clusters (566 dyads) to SQ-LNS and growth charts. SQ-LNS improved HAZ by 0.21 SD (95% CI 0.06 to 0.36) and reduced the odds of stunting by 37% (adjusted OR, aOR 0.63, 95% CI (0.46 to 0.87)). No HAZ or stunting impacts were found in the growth charts only or growth charts+SQ LNS arms. SQ-LNS only improved WAZ (mean difference, MD 0.17, 95% CI (0.05 to 0.28). No impacts on WAZ were seen for growth charts and the combined intervention. Child development was higher in the growth charts only (MD 0.18, 95% CI (0.01 to 0.35)) and SQ-LNS only arms (MD 0.28, 95% CI (0.09 to 0.46). SQ-LNS improved average haemoglobin levels (MD 2.9 g/L (0.2, 5.5). The combined intervention did not have an impact on WAZ, Hb or GSED but reduced the odds of anaemia (aOR 0.72, 95% CI (0.53 to 0.97)). No adverse events were reported.InterpretationSQ-LNS appears to be effective in reducing growth faltering as well as improving anaemia and child development. Growth charts also show the potential to reduce anaemia and improve child development but do not seem as effective in addressing growth faltering. Further research is needed to better understand reduced effectiveness when both interventions are combined.Trial registration numberNCT051204272.

Project description:Implementation research is concerned with bridging the gap between evidence and practice through the study of methods to promote the uptake of research into routine practice. Good quality evidence has been summarised into guideline recommendations to show that peri-operative fasting times could be considerably shorter than patients currently experience. The objective of this trial was to evaluate the effectiveness of three strategies for the implementation of recommendations about peri-operative fasting.A pragmatic cluster randomised trial underpinned by the PARIHS framework was conducted during 2006 to 2009 with a national sample of UK hospitals using time series with mixed methods process evaluation and cost analysis. Hospitals were randomised to one of three interventions: standard dissemination (SD) of a guideline package, SD plus a web-based resource championed by an opinion leader, and SD plus plan-do-study-act (PDSA). The primary outcome was duration of fluid fast prior to induction of anaesthesia. Secondary outcomes included duration of food fast, patients' experiences, and stakeholders' experiences of implementation, including influences. ANOVA was used to test differences over time and interventions.Nineteen acute NHS hospitals participated. Across timepoints, 3,505 duration of fasting observations were recorded. No significant effect of the interventions was observed for either fluid or food fasting times. The effect size was 0.33 for the web-based intervention compared to SD alone for the change in fluid fasting and was 0.12 for PDSA compared to SD alone. The process evaluation showed different types of impact, including changes to practices, policies, and attitudes. A rich picture of the implementation challenges emerged, including inter-professional tensions and a lack of clarity for decision-making authority and responsibility.This was a large, complex study and one of the first national randomised controlled trials conducted within acute care in implementation research. The evidence base for fasting practice was accepted by those participating in this study and the messages from it simple; however, implementation and practical challenges influenced the interventions' impact. A set of conditions for implementation emerges from the findings of this study, which are presented as theoretically transferable propositions that have international relevance.ISRCTN18046709--Peri-operative Implementation Study Evaluation (POISE).

Project description:BackgroundDupuytren's contracture is a fibro-proliferative disease of the hands affecting over 2 million UK adults, particularly the white, male population. Surgery is the traditional treatment; however, recent studies have indicated that an alternative to surgery-collagenase clostridium histolyticum (collagenase)-is better than a placebo in the treatment of Dupuytren's contracture. There is however no robust randomised controlled trial that provides a definitive answer on the clinical effectiveness of collagenase compared with limited fasciectomy surgery. Dupuytren's intervention surgery vs collagenase trial (DISC) trial was therefore designed to fill this evidence gap.Methods/designThe DISC trial is a multi-centre pragmatic two-arm parallel-group, randomised controlled trial. Participants will be assigned 1:1 to receive either collagenase injection or surgery (limited fasciectomy). We aim to recruit 710 adult participants with Dupuytren's contracture. Potential participants will be identified in primary and secondary care, screened by a delegated clinician and if eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported patient evaluation measure assessed 1 year after treatment. Secondary outcome measures include the Unité Rhumatologique des Affections de la Main Scale, the Michigan Hand Questionnaire, EQ-5D-5L, resource use, further procedures, complications, recurrence, total active movement and extension deficit, and time to return to function. Given the limited evidence comparing recurrence rates following collagenase injection and limited fasciectomy, and the importance of a return to function as soon as possible for patients, the associated measures for each will be prioritised to allow treatment effectiveness in the context of these key elements to be assessed. An economic evaluation will assess the cost-effectiveness of treatments, and a qualitative sub-study will assess participants' experiences and preferences of the treatments.DiscussionThe DISC trial is the first randomised controlled trial, to our knowledge, to investigate the clinical and cost-effectiveness of collagenase compared to limited fasciectomy surgery for patients with Dupuytren's contracture.Trial registrationClinical.Trials.gov ISRCTN18254597 . Registered on April 11, 2017.

Project description:BackgroundAlmost a quarter of the world's undernourished people live in India. We tested the effects of three nutrition-sensitive agriculture (NSA) interventions on maternal and child nutrition in India.MethodsWe did a parallel, four-arm, observer-blind, cluster-randomised trial in Keonjhar district, Odisha, India. A cluster was one or more villages with a combined minimum population of 800 residents. The clusters were allocated 1:1:1:1 to a control group or an intervention group of fortnightly women's groups meetings and household visits over 32 months using: NSA videos (AGRI group); NSA and nutrition-specific videos (AGRI-NUT group); or NSA videos and a nutrition-specific participatory learning and action (PLA) cycle meetings and videos (AGRI-NUT+PLA group). Primary outcomes were the proportion of children aged 6-23 months consuming at least four of seven food groups the previous day and mean maternal body-mass index (BMI). Secondary outcomes were proportion of mothers consuming at least five of ten food groups and child wasting (proportion of children with weight-for-height Z score SD <-2). Outcomes were assessed in children and mothers through cross-sectional surveys at baseline and at endline, 36 months later. Analyses were by intention to treat. Participants and intervention facilitators were not blinded to allocation; the research team were. This trial is registered at ISRCTN, ISRCTN65922679.Findings148 of 162 clusters assessed for eligibility were enrolled and randomly allocated to trial groups (37 clusters per group). Baseline surveys took place from Nov 24, 2016, to Jan 24, 2017; clusters were randomised from December, 2016, to January, 2017; and interventions were implemented from March 20, 2017, to Oct 31, 2019, and endline surveys done from Nov 19, 2019, to Jan 12, 2020, in an average of 32 households per cluster. All clusters were included in the analyses. There was an increase in the proportion of children consuming at least four of seven food groups in the AGRI-NUT (adjusted relative risk [RR] 1·19, 95% CI 1·03 to 1·37, p=0·02) and AGRI-NUT+PLA (1·27, 1·11 to 1·46, p=0·001) groups, but not AGRI (1·06, 0·91 to 1·23, p=0·44), compared with the control group. We found no effects on mean maternal BMI (adjusted mean differences vs control, AGRI -0·05, -0·34 to 0·24; AGRI-NUT 0·04, -0·26 to 0·33; AGRI-NUT+PLA -0·03, -0·3 to 0·23). An increase in the proportion of mothers consuming at least five of ten food groups was seen in the AGRI (adjusted RR 1·21, 1·01 to 1·45) and AGRI-NUT+PLA (1·30, 1·10 to 1·53) groups compared with the control group, but not in AGRI-NUT (1·16, 0·98 to 1·38). We found no effects on child wasting (adjusted RR vs control, AGRI 0·95, 0·73 to 1·24; AGRI-NUT 0·96, 0·72 to 1·29; AGRI-NUT+PLA 0·96, 0·73 to 1·26).InterpretationWomen's groups using combinations of NSA videos, nutrition-specific videos, and PLA cycle meetings improved maternal and child diet quality in rural Odisha, India. These components have been implemented separately in several low-income settings; effects could be increased by scaling up together.FundingBill & Melinda Gates Foundation, UK AID from the UK Government, and US Agency for International Development.

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TAME trial: a multi-arm phase II randomised trial of four novel interventions for malnutrition enteropathy in Zambia and Zimbabwe - a study protocol.

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TAME trial: a multi-arm phase II randomised trial of four novel interventions for malnutrition enteropathy in Zambia and Zimbabwe - a study protocol.

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