Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and asperin, versus IVIG and asperin for prevention of coronary artery aneurysm (CAA) in Kawasaki disease (KD)

Kawasaki disease (KD) is an acute self-limiting inflammatory vasculitis
affecting predominantly
medium-sized arteries, particularly the coronary arteries causing coronary
artery aneurysms (CAA). KD is currently the commonest cause of acquired heart
disease in children in high-income countries. KD causes CAA in 15-25% of
untreated patients while 2-3% of untreated cases die
as a result of coronary vasculitis [1, 5-7]. Coronary artery vasculitis can
cause acute myocardial events
in the early stages of the disease leading to myocardial infarction or even
death [1, 5-7]. Late morbidity
can also arise from late KD vasculopathy, a process involving remodelling
following the acute
inflammatory event, distinct from atherosclerosis, but ultimately leading to
coronary vascular
insufficiency and late cardiac events [1, 5-7]. Notably, as more children with
KD survive into adulthood,
the disease remains an important cause of long-term cardiac disease in
adulthood and requires
rigorous follow-up, particularly for those with CAA, to reduce risk of
myocardial ischaemia and
infarction.
The disease has a world-wide distribution with a male preponderance (male:
female ratio of 1.5:1,
seasonality and occasional epidemics. KD is more prevalent in Japanese children
(308/100,000
under the age of five years) [8]. An increased incidence of KD is also observed
in Japanese and other
Asian children resident in North America and Europe, suggesting a genetic
contribution [8-10]. In the
UK, a recent direct British Paediatric Surveillance Unit epidemiological survey
(2013-2015) showed
that the incidence of KD in the UK and Ireland was 4.55/100,000 children under
5 years, which
represents a slight increase since the last survey in 1990 [7, 11]. Whilst the
majority of cases were
Caucasian, KD in the UK is over-represented in Chinese or Japanese Asians and
Black Africans [7]. Other
recent studies have demonstrated a higher incidence of KD of 25/100,000
children <5 years in the US
[1]; and 5.5/100,000 children < 5 years in Skane, Sweden [12]. Mortality of KD
varies by population:
0.015% in Japan; 0.17% in the USA and 0.36% in the UK .

The overarching goal is to optimise the treatment of KD in children/adolescents
across Europe.
KD-CAAP will test the hypothesis that adding immediate adjunctive
corticosteroid treatment to IVIG
and aspirin will reduce CAA rates in unselected KD patients across Europe
compared with IVIG and
aspirin alone.
The primary aim of the KD-CAAP trial is therefore to establish:
1. the effectiveness and efficacy of adjunctive corticosteroid therapy combined
with IVIG/aspirin for
prevention of CAA in unselected patients with KD across Europe;
Secondary aims are to establish:
2. the safety of adjunctive corticosteroid therapy combined with IVIG/aspirin
for prevention of CAA
in KD;
3. whether adjunctive corticosteroid therapy reduces the duration of fever and
length of
hospitalisation for patients with KD;
4. the incremental cost-effectiveness ratio for corticosteroid therapy,
expressed as the cost per
QALY gained, from cost and utility data measured via resource use forms and the
Child Health
Utility 9D questionnaire.
5. the utility of the Paediatric Glucocorticoid Toxicity (pGTI) tool to assess
corticosteroid toxicity.
KD-CAAP will therefore develop an evidence-base that will directly and
definitively inform European
guidelines for the treatment of KD, which at the moment only target
corticosteroids at patients
deemed high-risk based on pragmatic, consensus, but non evidence-based clinical
features that were
formulated as an interim measure pending clinical trials outside of Japan (such
as KD-CAAP) [5].
Therefore, beyond the trial, the results will directly influence European
clinical guidelines for the
treatment of KD, and additionally will likely have international impact beyond
Europe as well since
data from Russia and the US also suggest poor outcomes with IVIG alone.

Multi-centre, randomised, open-label, blinded endpoint assessed parallel group
trial

All patients will receive intravenous immunoglobulin (IVIG) at 2g/kg given as
per local
standard of care; and aspirin at a dose of 40 mg/kg/day until the patient is
afebrile for at
least 48 hours, thereafter at 3-5 mg/kg/day for at least 21 days after the
fever resolves as
per standard of care.
Patients will be randomised to
* Control group: no additional initial treatment
* Experimental group: additional oral prednisolone at 2 mg/kg/day or intravenous
methylprednisolone at 1.6 mg/kg/day if oral prednisolone is not tolerated.
In both groups, patients will be assessed at day 2 (+/-12h) and will receive a
second dose
of IVIG if they have CRP>50% of baseline and still > 10 mg/L, OR temperature
(T) >=38 °C.
At day 5 (+/-12h) further management is again dictated by temperature and CRP:
(i) If CRP<=10 mg/L and T<38 °C, no further additional treatment is required.
Aspirin
should be continued as per above, and children/adolescents in the experimental
group should begin tapering corticosteroids.
(ii) If CRP>10 mg/L (regardless of temperature) or T>=38 °C rescue treatment
should be
considered at discretion of local investigator.

1. IVIG is safe and standard of care. Side effects are generally rare,
reversible and mild. Risk of
blood product derived infection are minimal with modern screening and
processing of IVIG,
and since patients receive this for KD anyway, no extra risk from the trial
exists. Benefit is
prevention of coronary artery aneurysms which would have lifelong consequences,
as proven
by meta-analyses.
2. Aspirin is safe and standard of care. Side effects are generally rare,
reversible and mild. Risk
of Gastrointestinal bleeding is minimal in children at dose and duration used
for KD, and since
patients receive this for KD anyway, no extra risk from the trial exists.
Benefit is prevention of
coronary artery aneurysms when given with IVIG, which would have lifelong
consequences,
as proven by meta-analyses.
3. Prednisolone is standard of care for high-risk cases in Europe as
highlighted in the European
consensus SHARE guideline [5] and many patients receive this for KD, even
though there is
some degree of equipoise (and hence the need for the trial). Any side effects
at the doses and
duration used are minimal and a detailed commentary is provided in the
Information Sheet.
Mitigation of these is use of proton pump inhibitors, and close monitoring for
side effects
using the Paediatric Glucocorticoid Toxicity Index. Clinicians already use
prednisolone for
many paediatric indications, and are familiar with their therapeutic index.
4. Despite a number of comparative and non-comparative studies comparing the
impact of
steroids in KD [54], this potentially highly effective treatment is not
commonly used for the
treatment of KD. Several factors are likely to contribute - inability to
identify high-risk children
early on in the disease course, when the meta-analysis suggests benefits will
be greatest* lack
of clarity on wider benefits in terms of longer-term cardiovascular health in
children without
overt vasculitis (coronary artery aneurysms, CAA))* relative weakness of the
evidence base
with Randomised Controlled Trial evidence being relatively small* and concerns
about
generalisability of findings from Japanese studies on Japanese populations in
case ethnic
differences contribute to variable efficacy. The proposed trial would delineate
the evidence
supporting adjunctive corticosteroids (or not), in all patients with KD,
leading to a pragmatic
and easily implementable recommendation.
5. Epidemiological data suggest worse outcomes in terms of CAA for children
under 1 year but
there remains significant equipoise about the use of corticosteroids in this
age group,
therefore inclusion of these patients is still justified in this trial.
Randomisation will be
stratified however, to ensure an equal balance of children < 1 year in each
randomised group.
6. As there is no diagnostic test for KD the diagnosis relies on clinical
criteria. The inclusion
criteria to the trial allows patients with incomplete cases of KD to be entered
in to the trial
many patients (particularly infants under the age of 12 months) have some but
not all of the
clinical features of KD, but may still be at high risk of CAA.
7. There is minimal risk of the overall protocol treatment above routine
clinical care because all
patients are actively managed with IVIG and aspirin. In addition clear criteria
for rescue
treatment are built into the trial design for both the control and experimental
groups. Trial
sites have considerable experience with managing patients with KD which will
minimise the
risks to the patients and the trial overall. We also established through a
survey coordinated
by the national c4c hubs and PRINTO that the trial protocol is acceptable with
no concerns
raised.
8. All children will be closely monitored so that side-effects are identified
at the earliest
opportunity and appropriate action taken. A detailed risk assessment was
conducted by the
MRC CTU at UCL prior to starting the trial which will inform the level of
monitoring required
and the proportion of on-site and central monitoring to ensure safety is being
reliably
assessed. Safety issues will be explicitly considered by the independent Data
Monitoring
Committee (DMC) who will review unblinded data regularly during the trial. The
DMC will
KD-CAAP Protocol
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Date 07-Apr-2021
MRC CTU at UCL Page 32
oversee all aspects of safety also taking into account any new data arising
from other studies
worldwide. The DMC will have a charter clearly setting out their roles and
responsibilities.
Serious adverse events will be reported to MRC CTU at UCL within 24 hours of
becoming aware
of the event* this responsibility will lie with site PIs and co-PIs, but may
also be delegated to
the Trial Physicians. The protocol contains a relatively short duration of
corticosteroid
treatment (in the experimental arm). We will systematically screen for
corticosteroid toxicity
using the newly formed Paediatric Glucocorticoid Toxicity Index, a variation of
the adult tool
we helped develop.
9. As children will be involved (aged 30 days to 15 years inclusive) consent
will be obtained from
parents or carers and assent from children (dependent the acuity of illness and
local
requirements). They will be provided information on the purpose and nature of
the research,
what it involves including the risks and benefits to make an informed decision
of their child to
be involved. Due to the acute nature of KD consent will be required promptly
after KD
diagnosis, a short trial introductory leaflet may initially be given to a
potential patients parent
or carer after consideration and if requested the informed consent form will be
given to the
parent/carer to provide consent.
10. For laboratory tests and storage samples collected within the trial the
child/adolescent will
give blood. This may result in unwanted adverse effects. The blood drawn during
the trial has
been limited and where possible will be taken at the same time as standard
clinical
monitoring. Local anaesthetic creams or sprays routinely used for blood draws
may also be
used. Many children will be in hospital for the first 5-7 days when the
majority of blood draws
will be made and will have a cannulae for medication through which the blood
draws will be
made.
11. For children/adolescents randomised to receive corticosteroids, there will
be a slight oral
medication burden in addition to/over standard of care. However, this is will
be for a limited
time period as once the child/adolescent's fever has resolved and their CRP is
equal to or less
than 10, after Day 5 the dosing of corticosteroids is tapered. A diary card
will be completed by
parents to record doses taken by their children to determine their adherence.
COVID specific benefit-risk assessment
The safety of subjects participating in KD-CAAP is of primary importance to the
sponsor. The risks of
subjects* involvement in KD-CAAP were specifically assessed in the context of
the ongoing global
COVID-19 pandemic and the applicable precautionary response measures in place
at the local or
national level. Risks to subjects were assessed against the anticipated benefit
of KD-CAAP participation
for subjects in accordance with International Council for Harmonisation (ICH)
Good Clinical Practice
(GCP) E6 (principle 2.2), and risks to quality were also assessed in accordance
with ICH GCP E6 (Section
5). Clinical trial management requirements for KD-CAAP were also assessed
against the European
Medicines Agency guidance on the management of clinical trials during the
COVID-19 pandemic
(European Medicines Agency 2020).
The Sponsor have established measures to ensure that the conduct of KD-CAAP
prioritizes the safety
of subjects and the integrity of clinical data. These measures were based on a
risk assessment of the
impact of COVID-19 on subject safety and on clinical trial conduct. The
specific measures established
for all subjects and investigative sites participating in KD-CAAP ar