Myechild01: International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia

Sponsor

University of Birmingham (Other)

Overall Status

Recruiting

CT.gov ID

NCT02724163

Collaborator

Assistance Publique - Hôpitaux de Paris (Other), Cancer Research UK (Other), National Cancer Institute, France (Other), Pfizer (Industry)

700

Enrollment

Locations

Arms

200

Anticipated Duration (Months)

10.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is :

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

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukaemia	Drug: Gemtuzumab ozogamicin Drug: Liposomal daunorubicin Drug: Mitoxantrone Drug: Fludarabine Drug: Cytarabine Drug: Busulfan Drug: Cyclophosphamide	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

700 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia - Incorporating an Embedded Dose Finding Study for Gemtuzumab Ozogamicin in Combination With Induction Chemotherapy

Actual Study Start Date :

Apr 1, 2016

Anticipated Primary Completion Date :

Dec 1, 2031

Anticipated Study Completion Date :

Dec 1, 2032

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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).	Drug: Mitoxantrone DNA-reactive agent Drug: Cytarabine Pyrimidine nucleoside analogue, an antineoplastic agent.
Experimental: 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).	Drug: Liposomal daunorubicin Anthracycline (Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug. Drug: Cytarabine Pyrimidine nucleoside analogue, an antineoplastic agent.
Experimental: Gemtuzumab Ozogamicin Dose Finding Study 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.	Drug: Gemtuzumab ozogamicin Antibody-conjugated chemotherapy agent. Other Names: Mylotarg
Active Comparator: High dose 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).	Drug: Cytarabine Pyrimidine nucleoside analogue, an antineoplastic agent.
Experimental: Fludarabine & 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	Drug: Fludarabine A water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine. Drug: Cytarabine Pyrimidine nucleoside analogue, an antineoplastic agent.
Active Comparator: Myeloablative conditioning 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).	Drug: Busulfan Alkylsulfonate Drug: Cyclophosphamide A nitrogen mustard alkylating agent from the oxazaphosphorine group
Experimental: Reduced intensity conditioning 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).	Drug: Fludarabine A water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine. Drug: Busulfan Alkylsulfonate

Outcome Measures

Primary Outcome Measures

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 one 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.
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 three 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 24 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).
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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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 cardiotoxicity (R1, R2 & R4 only). [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.]
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.
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Women and Children's Hospital Adelaide	Adelaide		Australia
2	Queensland Children's Hospital	Brisbane		Australia
3	Monash Children's Hospital	Melbourne		Australia
4	Royal Childrens Hospital	Melbourne		Australia
5	John Hunter Children's Hopsital	New Lambton Heights		Australia
6	Perth Children's Hospital	Perth		Australia
7	Sydney Children's Hospital	Sydney		Australia
8	The Childrens Hospital At Westmead	Westmead		Australia
9	Centre Hospitalier Universitaire Amiens - Picardie	Amiens		France
10	Centre Hospitalier Universitaire D'angers	Angers		France
11	Centre Hospitalier Regional Universitaire Besancon - Hopital Jean Minjoz	Besançon		France
12	Centre Hospitalier Universitaire De Bordeaux - Hopital Pellegrin	Bordeaux		France
13	Centre Hospitalier Regional Universitaire Brest - Hopital Morvan	Brest		France
14	Centre Hospitalier Universitaire De Caen	Caen		France
15	Centre Hospitalier Universitaire De Clermont-ferrand	Clermont-Ferrand		France
16	Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfants	Dijon		France
17	Centre Hospitalier Universitaire De Grenoble	Grenoble		France
18	Hopital Jeanne Dr Flandre	Lille		France
19	Centre Hospitalier Universitaire De Limoges	Limoges		France
20	Centre Leon Berard	Lyon		France
21	Hopital De La Timone	Marseille		France
22	Centre Hospitalier Regional Universitaire Montpellier - Hopital Arnaud-de-villeneuve	Montpellier		France
23	Centre Hospitalier Universitaire De Nancy	Nancy		France
24	Centre Hospitalier Universitaire De Nantes	Nantes		France
25	Centre Hospitalier Universitaire De NICE	Nice		France
26	Hopital Armand Trousseau	Paris		France
27	Hopital Robert Debre	Paris		France
28	Hopital Saint Louis	Paris		France
29	Centre Hospitalier Universitaire De Poitiers	Poitiers		France
30	Chu De Reims	Reims		France
31	Centre Hospitalier Universitaire De Rennes - Hopital Sud	Rennes		France
32	Centre Hospitalier Universitaire De Rouen	Rouen		France
33	Centre Hospitalier Universitaire Saint-etienne	Saint-Étienne		France
34	Strasbourg Hautepierre	Strasbourg		France
35	Centre Hospitalier Universitaire De Toulouse - Hopital Des Enfants	Toulouse		France
36	Centre Hospitalier Regional Universitaire De Tours - Hopital Clocheville	Tours		France
37	Our Lady's Hospital for Sick Children	Dublin		Ireland
38	Starship Childrens Hospital	Auckland		New Zealand
39	Christchurch Hospital	Christchurch		New Zealand
40	Kantonsspital Aarau	Aarau		Switzerland
41	Universitäts-Kinderspital beider	Basel		Switzerland
42	Ospedale San Giovanni	Bellinzona		Switzerland
43	Inselspital Bern	Bern		Switzerland
44	Hug Hopitaux Universitaires De Geneve	Geneve		Switzerland
45	Centre Hospitalier Universitaire Vaudois Chuv Lausanne	Lausanne		Switzerland
46	Luzerner Kantonspital - Kinderspital Luzern	Lucerne		Switzerland
47	Ostschweizer Kinderspital	St. Gallen		Switzerland
48	University Children's Hospital Zurich	Zurich		Switzerland
49	Royal Belfast Hospital for Sick Children	Belfast	County Antrim	United Kingdom	BT12 6BE
50	Royal Aberdeen Children's Hospital	Aberdeen		United Kingdom	AB25 2ZG
51	Aberdeen Royal Infirmary, NHS Grampian	Aberdeen		United Kingdom	AB25 2ZN
52	Birmingham Children's Hospital NHS Foundation Trust	Birmingham		United Kingdom	B4 6NH
53	University Hospitals Bristol NHS Foundation Trust	Bristol		United Kingdom	BS1 3NU
54	Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust	Cambridge		United Kingdom	CB2 0QQ
55	Cardiff and Vale University Health Board, Noah's Ark Children's Hospital for Wales	Cardiff		United Kingdom	CF14 4XW
56	NHS Lothian, Royal Hospital for Sick Children	Edinburgh		United Kingdom	EH9 1LF
57	NHS Greater Glasgow and Clyde, The Royal Hospital for Children	Glasgow		United Kingdom	G51 4TF
58	Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust	Leeds		United Kingdom	LS9 7TF
59	Alder Hey Children's NHS Foundation Trust	Liverpool		United Kingdom	L12 2AP
60	University College London Hospitals NHS Foundation Trust	London		United Kingdom	NW1 2PG
61	The Royal Marsden NHS Foundation Trust	London		United Kingdom	SW3 6JJ
62	Great Ormond Street Hospital For Children NHS Trust	London		United Kingdom	WC1N 3JH
63	Royal Manchester Childrens' Hospital , Central Manchester University Hospitals NHS Foundation Trust	Manchester		United Kingdom	M13 9WL
64	The Newcastle Upon Tyne Hospitals NHS Foundation Trust	Newcastle		United Kingdom	NE7 7DN
65	Nottingham University Hospitals NHS Trust	Nottingham		United Kingdom	NG7 2UH
66	John Radcliffe Hospital, Oxford Radcliffe Hospitals NHS Trust	Oxford		United Kingdom	OX3 9DU
67	Sheffield Children's NHS Foundation Trust	Sheffield		United Kingdom	S10 2TH
68	Southampton University Hospitals NHS Trust	Southampton		United Kingdom	SO16 6YD