| Protocol No: | ECCT/21/02/04 | Date of Protocol: | 05-06-2020 |
| Study Title: | GASTROSAM Gastroenteritis: Rehydration of children with severe acute malnutrition |
| This is the second protocol amendment for the study.The changes are mainly administrative therefore, neither the purpose, procedure nor the population of the trial has been changed. The sample size and randomization remain the same. The amendments made include. i) Addition of one extra study site in Kenya (Coast General Teaching and Referral Hospital- Mombasa) ii) Addition of new study co-investigators. (Dr. Victor Bandika as the Site Principal Investigator and Laura Mwalekwa). iii) Change for the trial manager from Hellen Mnjalla to Emmanuel Oguda | |
| This is the third amendement to the study protocol.The modification made to the protocol includes;
1.Addition of extra study sites in Niger and Nigeria and the addition of the 2 new study coinvestigators
2. Change of primary endpoint for intravenous rehydration stratum from urinary output at 8
hours to mortality at 96 hours. Justification of changes are (under section 14 sample size
determination)
3. Increase in the total number of participants to be enrolled in the study with severe
dehydration from 136 to 272 while those with some dehydration remain at 64 making a
total of 336 children.
4. Clarification of follow up Day 7 and Day 28 (after enrolment) rather than post discharge as
incorrectly stated in the study protocol (summary page)
Forwarded: 18th April 2023
5. The anthropometry measurement to be collected daily during inpatient stay to record post-rehydration weight and MUAC.
6. If parental consent is approved for monitoring urine collection (to assess volume), as per the previous protocol version we will monitor this over the first 8 hours. We had indicated we will store a sample of urine at 1, 4 and 8 hours. We have removed the 4-hour sample storage from in the amended version.
7. Extension for the study period from 18 months to 36 months from the start of recruitment (in Kenya this was January 2021) to continue with the study activities across the proposed sites.
8. The total blood volume collected will be less now it is 9.0mls (originally it was 9. 5mls). Revision of the reimbursements rates from (Ksh. 650 to 700 for the Urban setting and Rural for the Ksh.350 to 500).
9. Update on the section of the ICF on who should have access the participant information collected.
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| Study Objectives: | 1.General Objectives:To compare in children with signs of severe dehydration secondary to gastroenteritis
In children with diarrhoea complicated by moderate or ‘some’ dehydration (see study population) and as follow on rehydration post-intravenous rehydration in those with severe dehydration whether oral rehydration with
2.Specific Objectives
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| Laymans Summary: | What is the problem/background? Worldwide, gastroenteritis is the second biggest cause of mortality (after acute respiratory illnesses) with the vast majority occurring in low resource settings such as sub-Saharan Africa.
For children with SAM the current WHO recommendations for rehydration of children with signs of severe dehydration and diarrhoea are exceptionally conservative and very controversial. First, recommendations for intravenous (iv) rehydration is restricted only to those with advanced shock, a group we have documented to have an exceptionally high mortality rate (82% Day 28 mortality) on current guidelines since they focusing on the exclusive use of oral rehydration using low-sodium ORS (ReSoMal). The guidelines lack relevant clinical studies, founded largely on a time-honored and strongly held belief that the malnourished heart is at risk of failure. Moreover, guidelines indicate SAM children have an inability to cope with sodium-rich solutions (expert opinion, with no published primary data) recommending a preference hypotonic (half strength Darrow’s or lactated Ringers) solutions for iv resuscitation.
What questions are we trying to answer? The overarching aim is to generate the relevant evidence for refinement of future guidelines, which children benefit from intravenous rehydration, the rate of rehydration and whether children with severe malnutrition should be managed by the same guideline as other children or by a dedicated guideline.
Where is the study taking place, how many people does it involve and how are they selected? The study will run for 18 months and will enrol children 6 months up to 12 years who are admitted to the paediatric wards in 3 sites, 2 sites in Uganda (Mbale regional referral hospital and Soroti regional referral hospital) and Kilifi county hospital will be the third site. We aim to enrol 136 children in the stratum with severe dehydration and an additional 64 children with some dehydration; overall 200 children through a randomization procedure.
What does the study involve for those who are in it?
What are the benefits and risks/costs of the study for those involved? There will be no direct benefits to participants in this study. Blood tests that are not part of the routine tests will be paid for by the research. Results of these tests will be available to the attending clinician treating and may be used to identify treatments required the urgency as well of required treatments. The study will cover transport costs for follow-up and parents/caregivers will receive appropriate compensation for time spent in bringing children for follow-up. During the follow up visits, which will last up to one hour, any illnesses identified will be treated or referred appropriately. Parents/guardian will also be given appropriate health education/health promotion messages during follow-up visits.
How will the study benefit society? The study will provide understanding on management of dehydration in severely malnourished children and provide insights for designing interventions to improve the care of this children.
When does the study start and finish? The study will start after scientific and ethical approval and will run for a period of 18 months.
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| 3 | Title: Gastroenteritis Rehydration Of children with Severe Acute Malnutrition. (GASTRO-SAM) Lay Title: Giving fluids to children admitted with malnutrition and diarrhoea What is the problem/background? Worldwide, diarrhoeal diseases are the second biggest cause of mortality (after acute respiratory illnesses) with the vast majority occurring in low resource settings such as sub-Saharan Africa. For children with Severe Acute Malnutrition (SAM) the current WHO recommendations for rehydration of children with signs of severe dehydration and diarrhoea are exceptionally conservative and very controversial. First, recommendations for intravenous (IV) rehydration is restricted only to those with advanced shock, a group we have documented to have an exceptionally high mortality rate (82% Day 28 mortality) on current guidelines since they focus on the exclusive use of oral rehydration using low-sodium ORS (ReSoMal). The guidelines lack relevant clinical studies, founded largely on a time-honored and strongly held belief that the malnourished heart is at risk of failure. Moreover, guidelines indicate SAM children have an inability to cope with sodium-rich solutions (expert opinion, with no published primary data) recommending a preference in solutions that are low in electrolytes (half strength Darrow’s or lactated Ringers) for iv resuscitation. What questions are we trying to answer? To determine the appropriate management of dehydration for children with Severe Acute Malnutrition and diarrhoea Where is the study taking place, how many people does it involve and how are they selected? The study will run for 36 months and will enrol children 6 months up to 12 years who are admitted to the paediatric wards in 7 sites, 2 sites in Uganda (Mbale Regional Referral Hospital and Soroti Regional Referral hospital),2 sites in Kenya (KEMRI Wellcome Trust Research Programme (KWTRP), Kilifi County Hospital (KCH) and Coast General Hospital, Mombasa), and MSF sites one in Nigeria and two in Niger. The two Kenyan sites have a lot of experience with research in severe malnutrition. All patients in Kilifi will be admitted in the High dependency unit and the general paediatric ward which have the capacity to enrol the target group. We aim to enrol 272 children in the stratum with severe dehydration and an additional 64 children with some dehydration: overall 336 children through a randomization procedure. What does the study involve for those who are in it? There will be two groups. Group A for children with severe dehydration only and group B for children with some dehydration. Group A • For the children with severe dehydration allocated to receive the current recommended WHO rehydration strategy for severe malnutrition, they will receive ReSoMal at a rate of 5mls/kg every 30 minutes for 2 hours. • For the children in the group receiving fluid quickly, the fluids will run over 3-6 hours depending on their age. They may also receive an extra one or two ‘rapid boluses’ of fluid in the first hour. • For the children in the slow arm, they will receive the same volume of fluid by drip but given more slowly over 8 hours, but not receive any initial ‘rapid boluses’ of fluid in the first hour. Group B Following resolution of severe dehydration and for those with some dehydration or moderate dehydration, the participants will receive one of the two options below oral fluids • standard WHO ORS given for non-malnourished (experimental) versus • WHO SAM recommended low-sodium rehydration solution called RESOMAL. • Aside from the clinical samples the study will take extra tablespoon of blood (approximately 9.0mls in total) including admission samples and at 8 hours for bedside test (lactate) and for storage (cardiac biomarkers) plus a urine sample. • If possible, children in the study will have a soft tube connected to a bag to monitor urine output accurately how they respond to rehydration fluids given and to take urine samples at 1hour, and 8 hours after admission. • During admission we will take measurements of your child’s weight and arm circumference on a daily basis. • Participants will be followed-up on day 7 and day 28 (after study enrollment- day 0). During the follow up visits less than a teaspoon of blood (3mls) will be taken for a blood test and malaria test for both visits. What are the benefits and risks/costs of the study for those involved? There will be no direct benefits to participants in this study. Blood tests that are not part of the routine tests will be paid for by the research. Results of these tests will be available to the attending clinician treating and may be used to identify treatments required the urgency as well of required treatments. The study will cover transport costs for follow-up and parents/caregivers will receive an out-of-pocket allowance to cover study related expenses incurred in bringing children for follow-up. During the follow up visits, which will last up to one hour, any illnesses identified will be treated or referred appropriately. Parents/guardian will also be given appropriate health education/health promotion messages during follow-up visits. How will the study benefit society? The study will provide understanding on management of dehydration in severely malnourished children and provide insights for designing interventions to improve the care of these children. When does the study start and finish? The study will start after scientific and ethical approval and will run for a period of 36 months overall. |
| Abstract of Study: |
Children hospitalized with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea (
The proposed GASTROSAM trial is the next step in reappraising current recommendations. We aim to evaluate standard (usually used in non-SAM children) liberal strategies for both iv and oral rehydration in SAM children with diarrhoea. This Phase II trial will generate feasibility, safety and preliminary data on survival to 7 days and 28 days of rehydration strategies incorporating two strata for management of (A) severe dehydration comparing both rates of rehydration and volume of iv replacement and (B) the composition of ORS for children with some dehydration (post iv-rehydration) designed as a partial factorial trial.
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3 watery stools/day) which is accompanied by poor outcomes (case fatality 21%). Rehydration guidelines for SAM are exceptionally conservative and controversial, as they rely upon expert opinion, recommending restriction of intravenous (iv) to cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Our research group have conducted previous research to show that hypotonic solutions for rehydration and shock management resulted in worse outcomes than isotonic Ringers Lactate. Also, an observational study was conducted in Mbale which incorporated detailed investigation of myocardial function and haemodynamic response to intravenous rehydration for SAM children with severe dehydration due to diarrhoea. This study showed a very high mortality of children managed in accordance to WHO SAM rehydration guidelines (80%) with echocardiographic evidence of fluid responsiveness with intravenous rehydration (i.e. that is was safe and resulted in a positive myocardial response to rehydration) but indicated children remained grossly ‘under-filled’, and concluded the need to assess more liberal volumes of fluid rehydration.