E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10023320 |
E.1.2 | Term | Kawasaki's disease |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Does the combination of corticosteroid and IVIG/aspirin reduce the rate of heart complications in children/adolescents with Kawasaki disease across Europe compared with IVIG/aspirin alone? |
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E.2.2 | Secondary objectives of the trial |
Does the combination of corticosteroid and IVIG/aspirin reduce the length of stay in hospital for children/adolescents with Kawasaki disease, and do their blood test results improve faster compared with IVIG/aspirin alone? What side effects do children/adolescents get with corticosteroids or other therapies to treat Kawasaki disease? Is the combination of corticosteroid therapy and IVIG/aspirin a cost effective treatment for the management of Kawasaki disease?
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacometric Substudy - Secondary analysis of pharmacodynamic (PD) endpoints for efficacy and corticosteroid toxicity (in the corticosteroid group) will be performed using a new, preliminary validated tool called the paediatric glucocorticoid toxicity index (pGTI). Drug dose will be taken as the input with an estimated parameter for the decay in drug effect being used as a proxy for PK (K-PD approach). The efficacy analysis will consider linear and nonlinear mixed effects models of coronary Z-score over time with multivariable covariate analysis. The model will aim to identify possible differences between groups, and dose response (IVIG and corticosteroid cumulative dosing) corrected for important covariates such as CRP, age etc. The pGTI evolution in time with also be modelled using either linear or nonlinear mixed effects. The composite pGTI score will be treated as both a continuous variable and we will also consider sub-score modelling to assess which items are most susceptible to change in short-course therapy, which may lead to refinement of the score itself.
Health Economics: Incremental costs and cost-effectiveness are included as secondary endpoints to estimate whether the use of adjunctive corticosteroids is a cost-effective intervention to prevent CAA in KD. The health economic analysis will adopt the perspective of healthcare providers in each country. The health care costs for each patient will be estimated by collecting the use of healthcare resources e.g. treatments, investigations, hospital admissions, and contacts with health professionals on CRFs. Country-specific unit costs to value this resource use will be obtained from published and administrative sources. Outcomes in the economic analysis will be measured in terms of the co-primary outcomes of the trial, and in terms of health-related quality of life (HRQL) and quality-adjusted life years (QALYs). Health utilities suitable for measuring HRQL and QALYs will be assessed at Day 0 and at least week 1 or 2 (depending on date of discharge) and weeks 6 and 12 using the Child Health Utility 9D (CHU9D) questionnaire to the parents/carers of all the participants and to the participants themselves if aged 8 years and over. The CHU9D has been validated for use in children and is available in multiple languages. EQ-5D-Y (youth version) will additionally be administered to children/adolescents aged 8 years and over, and is available in multiple languages.
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E.3 | Principal inclusion criteria |
1. Aged 30 days (post-natal age) to 15 years inclusive, and below the country-specific age of consent for the duration of the trial 2. KD defined in at least one of the three following ways (a) as per American Heart Association (AHA) criteria: namely fever for at least 5 days in addition to 4 of the following 5 clinical criteria: I. bilateral non purulent conjunctivitis ii. cervical lymphadenopathy iii. polymorphous skin rash iv. changes in lips or mucosa (strawberry tongue, red cracked lips, diffuse erythematous oropharynx) v. extremity changes (erythema, oedema of palms and soles in initial phase, and at convalescent stage skin peeling) (b) OR less than 5 days of fever but all 5 clinical criteria above (c) OR incomplete KD cases, as per a modified*AHA definition, namely: I. children/adolescents (>1 year old) with fever greater than or equal to 5 days AND at least 2 other compatible clinical criteria as listed above; OR infants ≤ 1 year old with fever greater than or equal to 7 days without other explanation; AND for both age groups ii. CRP ≥30 mg/L or erythrocyte sedimentation rate (ESR) ≥40 mm/hr (or both) AND for both age groups iii. EITHER the presence of any 3 or more of: anaemia for age (haemoglobin < lower limit of normal reference range for local laboratory) platelet count ≥450 x10⁹/L or <140 x10⁹/L; albumin <30 g/L; elevated ALT (> upper limit of normal reference range for local laboratory); white cell count ≥15 x10⁹/L; urine ≥10 white blood cells per high power field iv. OR abnormal echocardiogram compatible with KD but without established CAA, with ≥ 3 of the following suggestive features: decreased left ventricular function, mitral regurgitation, pericardial effusion, or dilated but non-aneurysmal coronary arteries (internal diameter 2≤Z<2.5; and not meeting the exclusion criteria for aneurysmal change as defined below). 3. Written informed consent from appropriate legal representative(s), and assent from patients who have not reached the age of consent and will not reach the age of consent for the duration of the trial in the participating country, but are judged to have capacity for this (depending on both age and acuity of illness)
*This definition of incomplete KD is modified from the AHA definition by firstly, the exclusion of aneurysmal coronary artery changes as the sole echo finding, since this is an exclusion criterion for KD-CAAP, and secondly the inclusion of low platelet count as well as high platelet count, as highlighted in recent European consensus SHARE guideline.
Note that patients with KD can still be included in KD-CAAP if they have started IVIG treatment, as long as they are randomised no more than 24 hours after the IVIG infusion is initiated (see exclusion criteria below).
Test results must be from tests done on the calendar day of randomisation or the day before.
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E.4 | Principal exclusion criteria |
Disease-related exclusions: 1. This diagnosis is a second or further episode of KD. 2. Already established CAA at screening. 3. Severe Congestive Heart Failure or cardiogenic shock defined as the presence of hypotension and shock requiring the initiation of volume expanders. 4. Known congenital coronary artery abnormality that would impair assessment of the primary endpoint. 5. Suspected macrophage activation syndrome.
Exclusions related to medications: 6. Started IVIG more than 24 hours prior to randomisation. 7. Known hypersensitivity to prednisolone or methylprednisolone, or known phenylketonuria to aspartame used in a formulation in an infant less than 12 weeks 8. Current oral, intravenous or intramuscular corticosteroid treatment for more than 3 days in previous 7 days prior to randomisation. 9. History of previous severe reaction to any human immune globulin preparation. 10. Known contraindication to the study medication (refer to section 5.11 for study medication contraindications) 11. pGFR <30 ml/min/1.73 m2 (using the locally derived Haycock-Schwartz calculation see Appendix 2 for the formula)
Exclusions related to general health or other issues: 12. Active varicella zoster virus infection; or known exposure to a case of varicella within the previous 21 days prior to randomisation if known to be non-immune. 13. Co-enrolment in another study/trial of an investigative medicinal product. 14. Pregnant or/and breastfeeding adolescents 15. FEMALES ONLY: females of child-bearing potential not willing to use highly effective contraception during participation in the study (refer to section 5.9.2 for highly effective contraception methods). 16. Body weight <5kg
A blood or urine pregnancy test must be completed on the day or day before randomisation for adolescents who have begun menstruation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
KD-CAAP will have two co-primary outcome measures: Any CAA (definition below) 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 randomised groups).
An average estimate across weeks 1, 2, and 6 of the maximum of the 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 direct efficacy of corticosteroids).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Efficacy At each of weeks 1, 2, 6 and 12 individually, the maximum of the Z-score of the internal diameters of the proximal right coronary artery or left anterior descending coronary artery. Any CAA defined using a stricter definition of a luminal internal diameter Z-score of ≥2.5 alone documented within the 12 weeks of trial follow-up Receipt of rescue treatment. Receipt of second dose of IVIG. Duration of fever after enrolment (time to temperature <38°C). Daily serum concentrations of CRP from days 1-5, and at 1 and 2 weeks after enrolment, and time to normalisation of CRP (≤10mg/L). Duration of hospitalisation. Safety Serious adverse events including deaths. Grade 3 or 4 adverse events. Clinical adverse events of any grade judged related to IVIG, aspirin or corticosteroids.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Days 1, 2, 3, 4, 5 and weeks 1, 2, 6, 12 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard of care (IVIG and aspirin only) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
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E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Czechia |
Estonia |
Finland |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial is defined as 12 months after the last scheduled follow-up visit of the last randomised participant. This is to ensure sufficient time for data submission, data cleaning, verification of queries, database lock and final analysis. Each site will be closed once data cleaning is completed at that site, and the relevant regulatory authorities and ethics committee will be informed. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 1 |