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Presentation prepared by Dr Omar Hasan Kasule Sr MB ChB (MUK), MPH
(Harvard), DrPH (Harvard) Professor of Epidemiology and Bioethics King Fahad
Medical City.
The Feast trial is a large randomized controlled trial in Africans hospitalized with severe illness
examining whether the addition
of
rapid fluid (fluid resuscitation or expansion) at admission to hospital standard
case management improves survival compared
to standard management alone.
More specially, the trial
has been designated with
the
aim of resolving the current debate over:
a) Whether rapid correction of intravascular volume, using colloidal or electrolyte solutions, is safe and improves both survival and neurological
outcome in children with severe falciparum
malaria, and
b) Whether this approach is preferable to slow restoration of total body water deficits, as suggested by other clinical researchers and currently recommended in international guidelines.
Why is this trial Important?
In sub-Saharan
Rapid fluid infusion to correct fluid deficits is a supportive treatment and is practiced routinely for the emergency management of children with severe illness. Currently, reticence to adopt this approach remains, and thus African hospital children are managed with little fluid or no additional fluid. If the benefits of rapid fluid infusion were shown, then the FEAST trial potentially save thousands of lives of young children annually.
DESIGN
A 3-am randomized open comparative trial of fluid resuscitation strategies: (1) immediate volume resuscitation with normal (0.9%) saline; (2) Immediate volume expansion with 5% human solution (HAS); (3) Maintenance fluids, with no immediate volume expansion.
OUTCOME MEASURES
Primary Endpoint: in-hospital mortality at 48 hours after randomization, Secondly Endpoints: Mortality at 4 weeks, neurological sequelae at 4 weeks and 24 weeks, episodes of hypotensive shock within 48 hours of randomization, adverse events related to fluid resuscitation (pulmonary edema, intracranial hypertension or severe allergic reaction to those receiving albumin).
POPULATION
Inclusion criteria
Children aged > 60 days and < 12 years with severe febrile illness (impaired consciousness or respiratory
distress plus clinical
evidence of impaired perfusion.
Exclusion criteria
Children with
the
following conditions will be excluded: severe acute malnutrition; gastroenteritis;
chronic failure, pulmonary edema, and other conditions in which volume expansion is contraindicated; non-infectious causes of severe illness; children who have already received
an Isotonic volume expender
during the current illness.
TRIAL TREATMENT
2,880 eligible children will be randomly assigned in a ratio of 1; 1; 1 to one three fluid management
arms: (1)
Rapid volume expansion with 20mls/kg intravenous 0.9% saline; (2) Rapid volume expansion with 20mls/kg 5% human
albumin solution (HAS0); (3)Maintenance fluids with
no
volume expansion
(control
arm).
Children will be reassessed at 1, 4, 8, and 24 hours, and further fluids boluses will be given in strict accordance with the protocol.
Follow-up
Children will be clinically assessed at 1, 4, 8, and 24 hours. Neurological assessment will be carried out at 4 weeks and for those with the sequel at 4 weeks from the time of randomization, Follow-up neurological assessment will be carried out by a clinician nurse who is blind to treatment allocation.
Informed
Consent Process
Before 1996,
there was no provision in international regulations allowing any exception from the
informed
consent requirement, for greater than minimal risks emergency research. New regulations, brought in 1996, by the United
States Food
and Drug Administration (FDA), provided
an opportunity for
research to proceed without consent and
designated such exemptions from informed consent (EFIC)
The key elements of the exclusion from informed consent (EFIC) Final Rule Include: 1) the subject has an immediately life-threatening condition; 2) available treatments are unproven or unsatisfactory; 3) consent from the subject (or a surrogate) is not feasible due to the urgency to the patients/subject’s condition; 4) the research could not otherwise be performed; 5) the risks and benefits are reasonable; and 6) there is a prospect the trial will be of direct medical benefit to the patient/subject. An additional requirement is a consultation with the community from which subjects will be drawn, including public disclosure of the study design and risks prior to commencement.
In the setting of resuscitation research, all potential subjects are vulnerable by virtue of their lack of capacity to understand or communicate opinions regarding their participation in research, in the case of a child who requires resuscitation, the accompanying parent or guardian acts as a surrogate. However, adequately informed permission, even by a surrogate decision-maker, is often impossible within the short therapeutic window required for successful intervention for example, in the situations such as cardiac arrest, status epilepticus, or life-threatening shock. Moreover, vulnerability also extends to surrogate decision-makers in an emergency situation and undermines their ability to make an informed choice. In these situations, the requirement for informed and voluntary parental permission may introduce a selection bias undermining the generalizability and feasibility of answering specific research objectives.
In the case of a pediatric fluid
resuscitation trial for
the
treatment of
shock, the requirement for
IC would mean
that in life-threatening emergencies, the group which provides the most informative data on
different intervention strategies would be excluded by virtue of their surrogate’s vulnerability. Resulting in a trial conducted in ales
critically ill cohort of children whose data may be less informative or even
misleading for severely ill children.
For the design and conduct
of FEAST, the investigators considered that reading or having read (in the cases of illiterate parents) lengthy information sheets to a distressed parent would not result in a ‘fully informed’ decision. The decision-makers would be
left with insufficient time to weigh up risks and benefits, and may inadvertently be instituting treatment, which would
be
ethically unacceptable.
They therefore concluded
that the use of deferred
consent would be appropriate for some but not all of
the
potential participants, Children who were stable enough to allow time for the consent process or whose surrogate decisions makers were not too distressed to understand
the
information, ask questions
and give or
decline consent would
follow the standard consent process.
For other children, the investigators develop a process of deferred consent that incorporated verbal
parental or guardian
assents.
1. The surrogate decision makers of potentially eligible children would be informed at admission
that in addition to standard care, their child may be involved in the research but not if they
chose to opt out.
2. For children
who
are eligible to be enrolled, study nurses would like to decide which parents would
be
able to give full
consent at the time of enrollment and which parents would be too distressed to participate in the full consent process and hence, would go through an assent process. Subsequently, these parents would receive information conveyed by a short verbal ‘assent’ process conducted at the point of enrollment by specially trained study clinicians or nurses. The information given during the verbal
assent process includes key elements of ICH-GCP
(detailed in
3. Verbal assent to the research, including randomization is followed
by
the full details
of the study
and a request for
formal written consent only when the child's medical
condition
has
become less critical.
Deferred consent, therefore, encompasses all the required
messages and
elements present in
standard consent, the difference being that the process is split to give the minimum information
verbally and followed
by
full details later once logistically
or justly appropriate.
If any enrolled children die prior to parents being able to receive full information about the study, it was decided that it would be inhumane to subject emotionally distressed parents to a full consent process.
- We are going to provide the treatment for your child that is recommended by the government.
- We want to find out if we can improve on these current recommendations by trying new treatments that we think will work better. We do this by research.
- All research is checked by independent committees to make sure that the potential benefits to individuals outweigh the risks. All participation in research is voluntary, so you can refuse.
- We would like your child to participate in research for us to learn the best to give fluids to every sick child.
- Do you agree for your child to take part in this research? You can say no and your child will still receive the same level of care with the government's recommended
treatment.
Questions:
- Comment on any aspect of the informed consent or assent process.
- Comment on
the
information given at
the time of assent (
- Comment on the procedure regarding not asking for full informed consent from surrogates whose child has early mortality.