Trial Summary

Information Type	Summary Details
Short title	KD-CAAP (Kawasaki Disease Coronary Artery Aneurysm Prevention trial)
Long Title of Trial	Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysms (CAA) in Kawasaki disease (KD)
Current Protocol Version	5.0
Date	22 October 2021
ISRCTN #	ISRCTN71987471
EudraCT #	2019-004433-17
Trial Design	Multi-centre, randomised, open-label, blinded endpoint assessed parallel group trial
Setting	Hospitals in Europe
Type of Participants to be Studied	Patients aged 30 days to 15 years inclusive, with Kawasaki disease (KD) defined by the American Heart Association (AHA) criteria [1] which includes: fever for at least five days in addition to 4 of 5 additional criteria, or less than 5 days of fever but otherwise meeting all five AHA clinical criteria, or incomplete KD cases, as per a modified AHA definition. Patients can be recruited even if they have already received IVIG as long as they are randomised no more than 24 hours after IVIG was initiated.
Interventions to be Compared	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 either: 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.
Trial Hypothesis	Adding immediate corticosteroid treatment to standard of care IVIG and aspirin will reduce coronary artery aneurysm (CAA) rates in unselected KD patients across Europe compared with IVIG and aspirin alone.
Primary Outcome Measure(s)	KD-CAAP will have two co-primary outcome measures based on repeat echocardiography undertaken at weeks 1, 2, 6 and 12 weeks: (i) Any CAA documented within the 12 weeks of trial follow-up (to assess overall effectiveness of the strategy of immediate corticosteroids in preventing CAA, expecting that some patients will receive rescue treatment before reaching this endpoint in both groups) (ii) An average estimate across weeks 1, 2, and 6 of the maximum Z-score of the internal diameters of the proximal right coronary artery or left anterior descending coronary artery, adjusting for rescue treatment (to assess the efficacy of corticosteroids).
Secondary Outcome Measure(s)	Efficacy secondary outcomes (i) At each of weeks 1, 2, 6 and 12 individually, the maximum coronary Z-score (ii) CAA defined solely by a luminal internal diameter z-score of ≥2.5 (iii) Receipt of rescue treatment (iv) Receipt of second dose of IVIG (v) Duration of fever after enrolment (time to temperature <38 °C) (vi) Daily serum concentrations of CRP from days 1-5, and at 1 and 2 weeks after enrolment, and time to normalisation of CRP (≤10 mg/L) (vii) Duration of hospitalisation Safety secondary outcomes (viii) Serious adverse events including deaths (ix) Grade 3 or 4 adverse events (x) Clinical adverse events of any grade judged related to IVIG, aspirin or corticosteroids
Other outcomes	(i) Changes in other laboratory parameters of inflammation (ii) Duration of corticosteroid therapy (iii) Cumulative weight adjusted dose of prednisolone or methylprednisolone received (iv) Proportion of patients who need to continue prednisolone at 2 mg/kg/day beyond day 5 within the experimental group (v) Paediatric appropriate health-related quality of life scores (vi) Paediatric corticosteroid toxicity index (pGTI) to assess glucocorticoid related morbidity [2] (vii) Incremental costs and cost-effectiveness; budget impact.
Randomisation	Patients who fulfil the eligibility criteria and have provided informed consent will be randomised 1:1 to receive immediate adjunctive open-label corticosteroids or not, plus standard of care IVIG and aspirin. Minimisation (with a random element) will be used to force balance between randomised groups (i.e. stratify randomisation) according to country, age (<1 versus ≥1 years) and sex.
Number of Participants	262 children/adolescents with KD (131 in each group)
Duration	Each child/adolescent will be followed for 12 weeks from randomisation. The trial will recruit over 30 months.
Sub-studies	Health economics: to estimate whether the use of adjunctive corticosteroids is a cost-effective intervention to prevent CAA in KD. Pharmacometric analysis: to estimate associations between drug doses and pharmacodynamic (PD) endpoints for efficacy and corticosteroid toxicity (in the experimental group). Biomarker signatures: to validate a 13-transcriptomic signature that distinguishes patients with KD from patients with bacterial, viral, and other inflammatory illnesses [3].
Funder	Innovative Medicines Initiative 2 Joint Undertaking (JU), under grant agreement No 777389 that supports the Conect4children (c4c) research consortium
Sponsor	University College London
Chief Investigators	Professor Despina Eleftheriou, Professor Paul Brogan