International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia

Phase 3

Recruiting

• Conditions: Acute Myeloid Leukaemia
• Interventions: Drug: Mitoxantrone; Drug: Liposomal daunorubicin; Drug: Gemtuzumab ozogamicin; Drug: Fludarabine; Drug: Cytarabine; Drug: Busulfan; Drug: Cyclophosphamide

• Registration Number: NCT02724163
• Lead Sponsor: University of Birmingham

Brief Summary

The main purpose of this study is :

1. To establish which number of doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) is tolerated and can be safety delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction

2. To compare mitoxantrone (anthracenedione) \& cytarabine with liposomal daunorubicin (anthracycline) \& cytarabine as induction therapy. (Randomisation 1 (R1) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.)

3. To compare a single dose of gemtuzumab ozogamicin with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy.

4. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine \& cytarabine (FLA) in standard risk patients.

5. To compare the toxicity and effectiveness of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conventional myeloablative conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.

Detailed Description

MyeChild 01 is an international phase III clinical trial in children with acute myeloid leukaemia (AML); a disease with significant mortality. It will compare two induction chemotherapy regimens: mitoxantrone and cytarabine (current standard treatment) with liposomal daunorubicin and cytarabine. This will test liposomal daunorubicin, which is believed to be less cardiotoxic than similar conventional drugs, although this is unproven. (Randomisation 1 (R1) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.)

Patients responding well to induction chemotherapy are eligible for a randomisation of two consolidation regimens: high dose cytarabine (current standard treatment) or fludarabine and cytarabine (FLA); a regimen commonly used in patients with relapsed disease, testing whether FLA is more effective in front line therapy than standard consolidation treatment. Patients with cytogenetic features associated with a higher risk of relapse and those responding sub-optimally to induction treatment are candidates for haemopoietic stem cell transplant (HSCT) and are eligible for a randomisation comparing two HSCT conditioning regimens: myeloablative conditioning (MAC) (current UNited Kingdom (UK) standard) or reduced intensity conditioning (RIC). HSCT has not consistently shown benefit in high risk patients because the mortality associated with the procedure has outweighed the advantage from a reduction in relapse risk. This will test whether reducing the intensity of conditioning improves survival by reducing transplant related deaths without increasing the relapse rate. The trial incorporates a dose finding study for gemtuzumab ozogamicin. The aim is to identify the optimum tolerated number of doses of gemtuzumab ozogamicin (up to a total of 3 doses), which can be safely combined with either of the induction chemotherapy regimens and then to compare this number of doses with one dose of gemtuzumab ozogamicin. The intensity of treatment will be directed by cytogenetics/molecular genetics and response assessed by minimal residual disease (MRD) levels measured by flow cytometry and molecular methodology.

Study Timeline

• Study First Submitted: 2016-01-08
• Study First Submitted QC: 2016-03-24
• Study First Posted: 2016-03-31
• Study Start: 2016-04
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-30
• Last Update Posted: 2021-10-08
• Primary Completion: 2031-12
• Study Completion: 2032-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 700

Inclusion Criteria

Inclusion criteria for trial entry

• Diagnosis of acute myeloid leukaemia (AML) /high risk Myelodysplastic syndrome (MDS) (>10% blasts in the bone marrow)/isolated myeloid sarcoma (MS) (either de novo or secondary).
• Age <18 years at trial entry.
• No prior chemotherapy or biological therapy for AML/high risk MDS/isolated MS other than that permitted in the protocol.
• Normal cardiac function defined as fractional shortening ≥28% or ejection fraction ≥55%.
• Fit for protocol chemotherapy.
• Documented negative pregnancy test for female patients of childbearing potential.
• Patient agrees to use effective contraception (patients of child bearing potential).
• Written informed consent from the patient and/or parent/legal guardian.

Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study:

Centres must be formally activated in order to be take part in the embedded dose escalation study. Please contact the trial office for further information.

• Patient meets the inclusion criteria for trial entry.

• Age:

  • ≥12 months for the major dose finding study
  • ≥ 12 weeks and <12 months for the minor dose finding study

• Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2.

• Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age unless it is caused by leukaemic involvement or Gilbert's syndrome or similar disorder.

• Alanine transaminase (ALT) or aspartate transaminase (AST) ≤10 x ULN for age.

• Written informed consent from the patient and/or parent/legal guardian.

Inclusion criteria for treatment with gemtuzumab ozogamicin for patients not participating in the gemtuzumab ozogamicin dose finding study or R2.

• Patient meets the inclusion criteria for trial entry (section 4.1.1)

• Age:

  • ≥12 months
  • ≥ 12 weeks
  • ≥28 days and <12 weeks (patients will receive a maximum of one dose of gemtuzumab ozogamicin)

• Normal renal function, defined as calculated creatinine clearance ≥90 ml/min/1.73m2

• Normal hepatic function, defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age and not due to leukaemic involvement or Gilbert's syndrome or similar disorder

• ALT or AST ≤10 x ULN for age

• Written informed consent from the patient and/or parent/legal guardian

Inclusion criteria for participation in R2.(once open to randomisation in the applicable age group)

• Patient meets the inclusion criteria for trial entry

Patient age:

• ≥12 months
• ≥12 weeks (once R2 open in patients aged ≥12 weeks and <12 months)
• Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2.
• Normal hepatic function defined as total bilirubin ≤2.5 ULN for age and not due to leukaemic involvement or Gilbert's syndrome or similar disorder.
• ALT or AST ≤10 x ULN for age.
• Written informed consent from the patient and/or parent/legal guardian.

Inclusion criteria for participation in R3.

• Patient meets the inclusion criteria for trial entry

• Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial.

• Minimal residual disease (MRD) response (performed in MyeChild 01 centralised laboratories, see national MyeChild 01 Laboratory Manual):

  • Patients with good risk cytogenetics/molecular genetics and a MRD level <0.1% by flow after course 2, or a decrease in transcript levels of >3 logs after course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring or
  • Patients with intermediate risk cytogenetics/molecular genetics with a MRD level <0.1% by flow after course 1 and course 2, or a decrease in transcript levels of >3 logs after course 1 and course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring.

• Written informed consent from the patient and/or parent/legal guardian.

Inclusion criteria for participation in R4.

• Patient meets the inclusion criteria for trial entry

• Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with fludarabine, cytarabine & idarubicin (FLA-Ida) off trial.

• Patient is in complete remission (CR) or CR with incomplete blood count recovery (CRi) defined as <5% blasts confirmed by flow cytometry/ molecular/FISH in a bone marrow aspirate taken within 6 weeks prior to randomisation to R4.

• Patient meets one of the following criteria and is a candidate for HSCT as per the protocol:

  • High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi).
  • Intermediate risk cytogenetics with MRD >0.1% after course 1 and 2 measured by flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular MRD marker with a sensitivity of >0.1% may be used.
  • Good risk cytogenetics with flow MRD >0.1% confirmed by a decrease in molecular MRD of <3 logs or rising transcript levels after course 3 despite treatment intensification (FLA-Ida) and after discussion with the Clinical Co-ordinators.

• Availability of a 9-10/10 human leukocyte antigen (HLA) matched family or unrelated donor or 5-8/8 matched cord blood unit with an adequate cell dose as defined by the protocol section 17.1.

• Written informed consent from the patient and/or parent/legal guardian.

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Exclusion Criteria

Exclusion criteria for all randomisations

• Acute Promyelocytic Leukaemia.
• Myeloid Leukaemia of Down Syndrome.
• Blast crisis of chronic myeloid leukaemia.
• Relapsed or refractory AML.
• Bone marrow failure syndromes.
• Prior anthracycline exposure which would inhibit the delivery of study anthracyclines.
• Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML/high risk MDS/isolated MS.
• Pregnant or lactating females.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mitoxantrone	Mitoxantrone	Course 1 * Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2, 3 and 4 (total 4 doses). * Cytarabine:100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 * Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2 and 3 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).
Liposomal daunorubicin	Liposomal daunorubicin	Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug. Course 1 * Liposomal daunorubicin: 80 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 * Liposomal daunorubicin: 60 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).
Mitoxantrone	Cytarabine	Course 1 * Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2, 3 and 4 (total 4 doses). * Cytarabine:100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 * Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2 and 3 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).
Gemtuzumab Ozogamicin Dose Finding Study	Gemtuzumab ozogamicin	* Cohort 1: 1x3mg/m2 IV infusion over 2hours on day 4. * Cohort 2: 2x3mg/m2 IV infusion over 2hours on day 4 and day 7. * Cohort 3: 3x3mg/m2 IV infusion over 2hours on days 4, 7 and 10.
Liposomal daunorubicin	Cytarabine	Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug. Course 1 * Liposomal daunorubicin: 80 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 * Liposomal daunorubicin: 60 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).
Fludarabine & cytarabine	Fludarabine	Two courses of: * Fludarabine: 30 mg/m2 daily by IV infusion over 30 minutes on days 1-5 inclusive (total 5 doses). * Cytarabine: 2 g/m2 daily by IV infusion over 4 hours on days 1-5 inclusive (total 5 doses).The cytarabine infusion should be started 4 hours after the start of the fludarabine infusion
Fludarabine & cytarabine	Cytarabine	Two courses of: * Fludarabine: 30 mg/m2 daily by IV infusion over 30 minutes on days 1-5 inclusive (total 5 doses). * Cytarabine: 2 g/m2 daily by IV infusion over 4 hours on days 1-5 inclusive (total 5 doses).The cytarabine infusion should be started 4 hours after the start of the fludarabine infusion
High dose cytarabine	Cytarabine	Two courses of Cytarabine: 3 g/m2 12 hourly by IV infusion over 4 hours on days 1, 3 and 5 (total 6 doses).
Reduced intensity conditioning	Fludarabine	* Busulfan AUC60-65mg/L X hr by IV infusion over 3 hours, given 12 hourly on days -5 to -2 (8 doses). * Fludarabine 30mg/m2/day by IV infusion over 30 minutes on days -8 to -3 (6 doses).
Reduced intensity conditioning	Busulfan	* Busulfan AUC60-65mg/L X hr by IV infusion over 3 hours, given 12 hourly on days -5 to -2 (8 doses). * Fludarabine 30mg/m2/day by IV infusion over 30 minutes on days -8 to -3 (6 doses).
Myeloablative conditioning	Busulfan	* Busulfan Area Under the Curve (AUC) 70-100mg/L x hr by IV infusion over 3 hours, given 12 hourly on days -10 to -7 (8 doses). * Cyclophosphamide 50mg/kg/day by IV infusion over 1 hour, on days -5 to -2 (4 doses).
Myeloablative conditioning	Cyclophosphamide	* Busulfan Area Under the Curve (AUC) 70-100mg/L x hr by IV infusion over 3 hours, given 12 hourly on days -10 to -7 (8 doses). * Cyclophosphamide 50mg/kg/day by IV infusion over 1 hour, on days -5 to -2 (4 doses).

Primary Outcome Measures

Name	Time	Method
Incidence of dose limiting toxicities (DLTs).	Incidence of DLTs will be evaluated up to day 45 post course 1 and course 2 of induction chemotherapy.
Event Free Survival (EFS).	Event free survival (EFS) will be evaluated as the time from randomisation two to the first event, up to 16 years..	The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.
Relapse free survival (RFS).	Relapse free survival (RFS) will be evaluated as the time of randomisation four to the first relapse or death from any cause, up to 16 years.	The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. RFS estimates will be presented at 12 months along with 95% confidence intervals.
Early treatment related adverse reactions.	Early treatment related adverse reactions will be evaluated at day 100 post-transplant.	Early treatment related adverse reactions defined as the incidence by day 100 post-transplant of grade 3-5 toxicity for the following systems using the National Cancer Institute (NCI) Common Terminology Criteria v4: * Cardiac (pericardial effusion/Left ventricular systolic dysfunction).; * Respiratory, thoracic and mediastinal (hypoxia/pneumonitis).; * Gastrointestinal (GI) (diarrhoea/typhlitis/upper and lower GI haemorrhage).; * Investigations (bilirubin).; * Renal and Urinary (acute kidney injury/haematuria).; * Nervous system (seizure).

Secondary Outcome Measures

Name	Time	Method
Incidence of cardiotoxicity (R1, R2 & R4 only).	Evaluated 30 days after end of trial treatment.
The nature, incidence and severity of adverse events (AEs) (gemtuzumab ozogamicin dose finding study).	Evaluated by day 45 post course 1 and course 2.
Response measured by bone marrow assessment using morphology and minimal residual disease (MRD) assessment (gemtuzumab ozogamicin dose finding study).	Evaluated by day 45 post course 1 and course 2.	Response is assessed by morphology confirmed by MRD levels measured by flow cytometry, molecular methods or fluorescence in situ hybridisation (FISH) as defined in the protocol, in combination with platelet and neutrophil counts. These results of these assessments will be combined to determine the patient's disease response using the response criteria defined in the protocol.
Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Clearance (CL) (gemtuzumab ozogamicin dose finding study)	Evaluated up to one month after the first dose of gemtuzumab ozogamicin.	Serum PK parameters will be measured using serial samples taken at multiple timepoints during course 1 and at 1 month post first dose of gemtuzumab ozogamicin as defined in the protocol by dose cohort.
Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Volume of distribution (Vd) (gemtuzumab ozogamicin dose finding study)	Evaluated up to one month after the first dose of gemtuzumab ozogamicin.	Serum PK parameters will be measured using serial samples taken at multiple timepoints during course 1 and at 1 month post first dose of gemtuzumab ozogamicin as defined in the protocol by dose cohort.
Overall Survival (OS) (all randomisations).	Evaluated as time from randomisation to the relevant question to death from any cause or date last seen for patients who are alive at the end of the trial, up to 16 years.	The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. OS estimates will be presented at 24 months along with 95% confidence intervals for randomisations 1, 2 and 3, and at 12 months for randomisation 4.
Incidence of toxicities (all randomisations).	Evaluated 30 days after end of trial treatment.
Incidence of bilirubin of grade 3 of higher (R2 & R4 only).	Evaluated 30 days after end of trial treatment.
Complete remission (CR) (R1 & R2).	Evaluated and presented at the completion of course 1 and 2 of treatment up to a maximum of 45 days post each course of treatment	Evaluated using remission status at completion of course 1 and course 2.
Cumulative Incidence of Relapse (CIR) (all randomisations).	Evaluated as time from randomisation to the relevant question to relapse, up to 16 years.	The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. CIR estimates will be presented at 24 months along with 95% confidence intervals for randomisations 1, 2 and 3, and at 12 months for randomisation 4.
Reasons for failure to achieve CR (R1 & R2).	Evaluated and presented at the completion of course 1 and 2 of treatment, up to a maximum of 45 days post each course of treatment.	Evaluated as resistant disease, induction death or not evaluable.This will be evaluated at completion of course 1 and 2 of treatment, once patient's blood counts have recovered or reason for non-recovery has been determined.
Time to haematological recovery (all randomisations).	Evaluated by day 45 post course 1 and course 2.	Evaluated using the date of haematological recovery (platelets to \>=80 x 10\^9/L, and neutrophils to \>=1.0 x 10\^9/L). The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. Time to haematological recovery estimates will be presented at 45 days post course 1 and course 2 of treatment along with 95% confidence intervals.
Death in CR (DCR) (R1, R2 & R3).	Evaluated as time from randomisation to relevant question to date of death from any cause in patients who have achieved CR, up to 16 years.	The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. DCR estimates will be presented at 24 months along with 95% confidence intervals.
Event Free Survival (EFS) (R1, R2 & R3).	Evaluated as time from randomisation to the relevant question to the first of failure to achieve CR (recorded as an event on day 1), relapse, secondary malignancy or death from any cause, up to 16 years.	The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.
Incidence of Veno-Occlusive Disease (R2 & R4 only).	Evaluated 30 days after end of trial treatment.
Minimal Residual Disease (MRD) clearance after course 1 & 2 (R1 & R2 only).	Evaluated and presented at completion of course 1 and 2 of treatment, up to a maximum of 45 days post each course of treatment.	Evaluated using MRD result at completion of course 1 and 2 once patient's blood counts have recovered or reason for non-recovery has been determined.
Days in hospital after each course of treatment (all randomisations).	Evaluated once all patients have completed trial treatment.	Total number of days spent in hospital for each course of treatment, collected from date of randomisation until count recovery after final course of treatment, up to a maximum of 45 days post the final course of treatment. This will be summarised per course of treatment.
Incidence of mixed chimerism at day 100 post-transplant (R4 only).	Evaluated at day 100 post-transplant.
Treatment Related Mortality (TRM) (R4 only).	Evaluated as time in days between randomisation to R4 and death which is unrelated to the underlying disease and considered related to the transplant procedure.	The primary analysis will be carried out once the last patient has a minimum of 1 year follow up which is estimated to be 7 years after the start of recruitment. TRM estimates will be presented at 12 months along with 95% confidence intervals.
Gonadal function (R4 only).	Evaluated at 1 year post-transplant and at the end of follow-up, which is estimated to be through to study completion, an average timeframe of 10 years.	The method of assessment will be by scale (Tanner scale) and physiological parameters. This will be evaluated at 1 year post-transplant and at the end of study follow-up.

Trial Locations

Locations (68)

Monash Children's Hospital; 🇦🇺 Melbourne, Australia

Women and Children's Hospital Adelaide; 🇦🇺 Adelaide, Australia

Queensland Children's Hospital; 🇦🇺 Brisbane, Australia

Royal Childrens Hospital; 🇦🇺 Melbourne, Australia

Hopital De La Timone; 🇫🇷 Marseille, France

John Hunter Children's Hopsital; 🇦🇺 New Lambton Heights, Australia

Perth Children's Hospital; 🇦🇺 Perth, Australia

Sydney Children's Hospital; 🇦🇺 Sydney, Australia

The Childrens Hospital At Westmead; 🇦🇺 Westmead, Australia

Centre Hospitalier Universitaire D'angers; 🇫🇷 Angers, France

Centre Hospitalier Universitaire De Bordeaux - Hopital Pellegrin; 🇫🇷 Bordeaux, France

Centre Hospitalier Regional Universitaire Besancon - Hopital Jean Minjoz; 🇫🇷 Besançon, France

Centre Hospitalier Regional Universitaire Brest - Hopital Morvan; 🇫🇷 Brest, France

Centre Hospitalier Universitaire De Clermont-ferrand; 🇫🇷 Clermont-Ferrand, France

Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfants; 🇫🇷 Dijon, France

Centre Hospitalier Universitaire De Limoges; 🇫🇷 Limoges, France

Centre Leon Berard; 🇫🇷 Lyon, France

Centre Hospitalier Universitaire De Grenoble; 🇫🇷 Grenoble, France

Hopital Jeanne Dr Flandre; 🇫🇷 Lille, France

Centre Hospitalier Regional Universitaire Montpellier - Hopital Arnaud-de-villeneuve; 🇫🇷 Montpellier, France

Centre Hospitalier Universitaire De Nancy; 🇫🇷 Nancy, France

Centre Hospitalier Universitaire De NICE; 🇫🇷 Nice, France

Centre Hospitalier Universitaire De Nantes; 🇫🇷 Nantes, France

Hopital Armand Trousseau; 🇫🇷 Paris, France

Hopital Saint Louis; 🇫🇷 Paris, France

Centre Hospitalier Universitaire De Poitiers; 🇫🇷 Poitiers, France

Centre Hospitalier Universitaire Saint-etienne; 🇫🇷 Saint-Étienne, France

Centre Hospitalier Universitaire De Rennes - Hopital Sud; 🇫🇷 Rennes, France

Strasbourg Hautepierre; 🇫🇷 Strasbourg, France

Centre Hospitalier Universitaire De Toulouse - Hopital Des Enfants; 🇫🇷 Toulouse, France

Chu De Reims; 🇫🇷 Reims, France

Our Lady's Hospital for Sick Children; 🇮🇪 Dublin, Ireland

Starship Childrens Hospital; 🇳🇿 Auckland, New Zealand

Universitäts-Kinderspital beider; 🇨🇭 Basel, Switzerland

Centre Hospitalier Regional Universitaire De Tours - Hopital Clocheville; 🇫🇷 Tours, France

Kantonsspital Aarau; 🇨🇭 Aarau, Switzerland

Ospedale San Giovanni; 🇨🇭 Bellinzona, Switzerland

Christchurch Hospital; 🇳🇿 Christchurch, New Zealand

Centre Hospitalier Universitaire Vaudois Chuv Lausanne; 🇨🇭 Lausanne, Switzerland

Luzerner Kantonspital - Kinderspital Luzern; 🇨🇭 Lucerne, Switzerland

Ostschweizer Kinderspital; 🇨🇭 St. Gallen, Switzerland

University Children's Hospital Zurich; 🇨🇭 Zurich, Switzerland

Royal Belfast Hospital for Sick Children; 🇬🇧 Belfast, County Antrim, United Kingdom

Aberdeen Royal Infirmary, NHS Grampian; 🇬🇧 Aberdeen, United Kingdom

University Hospitals Bristol NHS Foundation Trust; 🇬🇧 Bristol, United Kingdom

Royal Aberdeen Children's Hospital; 🇬🇧 Aberdeen, United Kingdom

Cardiff and Vale University Health Board, Noah's Ark Children's Hospital for Wales; 🇬🇧 Cardiff, United Kingdom

Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust; 🇬🇧 Cambridge, United Kingdom

NHS Greater Glasgow and Clyde, The Royal Hospital for Children; 🇬🇧 Glasgow, United Kingdom

NHS Lothian, Royal Hospital for Sick Children; 🇬🇧 Edinburgh, United Kingdom

Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust; 🇬🇧 Leeds, United Kingdom

University College London Hospitals NHS Foundation Trust; 🇬🇧 London, United Kingdom

Alder Hey Children's NHS Foundation Trust; 🇬🇧 Liverpool, United Kingdom

The Royal Marsden NHS Foundation Trust; 🇬🇧 London, United Kingdom

Great Ormond Street Hospital For Children NHS Trust; 🇬🇧 London, United Kingdom

Royal Manchester Childrens' Hospital , Central Manchester University Hospitals NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom

The Newcastle Upon Tyne Hospitals NHS Foundation Trust; 🇬🇧 Newcastle, United Kingdom

Southampton University Hospitals NHS Trust; 🇬🇧 Southampton, United Kingdom

Inselspital Bern; 🇨🇭 Bern, Switzerland

Hug Hopitaux Universitaires De Geneve; 🇨🇭 Geneve, Switzerland

Centre Hospitalier Universitaire Amiens - Picardie; 🇫🇷 Amiens, France

Centre Hospitalier Universitaire De Caen; 🇫🇷 Caen, France

Hopital Robert Debre; 🇫🇷 Paris, France

Centre Hospitalier Universitaire De Rouen; 🇫🇷 Rouen, France

Birmingham Children's Hospital NHS Foundation Trust; 🇬🇧 Birmingham, United Kingdom

Nottingham University Hospitals NHS Trust; 🇬🇧 Nottingham, United Kingdom

John Radcliffe Hospital, Oxford Radcliffe Hospitals NHS Trust; 🇬🇧 Oxford, United Kingdom

Sheffield Children's NHS Foundation Trust; 🇬🇧 Sheffield, United Kingdom