Ear, Nose, and Throat Diseases

Nervous System Diseases

Symptoms and General Pathology

All Conditions

Substance Related Disorders

Wounds and Injuries

Hearing Loss

Deafness

Ototoxicity

Hearing Disorders

Ear Diseases

Otorhinolaryngologic Diseases

Sensation Disorders

Neurologic Manifestations

study of mutations of metabolic enzymes and membrane transport genes, which will be performed by sequencing.

Genetic study

study of mutations of the mitochondrial gene MT-RN1, which will be performed by sequencing.

Genetic study MT-RN1

A limited number of relatively contradictory studies have suggested that the development of serious ototoxicity in children treated with cisplatin or, more rarely, carboplatin could be partly related to genetic risk factors affecting detoxification enzymes and membrane transporters of platinum derivatives. The objective of this study is therefore to identify genetic variants associated with the development of platinum ototoxicity in patients treated with cisplatin or carboplatin (minimum follow-up of 3 years) for one of the following diseases: neuroblastoma, hepatoblastoma, retinoblastoma, malignant germ cell tumour, osteosarcoma, high-risk or recurrent Wilms' tumour, non-parameningealrhabdomyosarcoma. A total of 180 patients, corresponding to 60 cases with grade 3 or 4 ototoxicity and 120 controls with no signs of ototoxicity (separate complete audiograms for each ear) will be included. A saliva sample will be used to obtain DNA for pharmacogenetic studies. The value of this study will be to define a population at high risk of developing ototoxicity in order to adapt treatment, or even develop preventive treatment of ototoxicity based on antioxidant medications

* Platinum derivatives and their toxicity Cisplatin, carboplatin, and oxaliplatin are major cytotoxic agents used in the treatment of many types of cancer. They exert their cytotoxic action by forming DNA adducts. However, their structural differences confer different pharmacokinetic and pharmacodynamic properties, and especially different toxicity profiles. Cisplatin induces a risk of nephrotoxicity at all ages, peripheral neuropathy of the extremities in young adults and a risk of ototoxicity in children. Carboplatin is essentially haematotoxic and sometimes ototoxic (especially at high doses), while oxaliplatin is essentially neurotoxic. Ototoxicity is measured by pure-tone audiometry and is scored from grade 0 to grade 4, where grades 3 and 4 correspond to severe ototoxicity, according to the Brock grading system, the reference system for measuring ototoxicity at the time of treatment of these children and up until the present time (Brock et al., 1991) (Peters et al., 2000). Ototoxicity limits the cumulative dose of platinum derivatives in children. Cisplatin remains a major drug in paediatric oncology (osteosarcoma, high-risk neuroblastoma, malignant germ cell tumours, hepatoblastoma, medulloblastoma, other brain tumours). Cisplatin ototoxicity is fairly frequent and can be very severe (more than 50% of grade 1 or higher ototoxicity; 15% of grade 3 or 4 ototoxicity) (Bertolini et al., 2004). Carboplatin, an important component of the treatment of many embryonal tumours (neuroblastoma, medulloblastoma, retinoblastoma) is less frequently responsible for ototoxicity (between 1 and 5% of grade 1 or higher ototoxicity), but can nevertheless occasionally cause serious ototoxicity (1% of grade 4) (Jehanne et al., 2009). Ototoxicity can also appear and deteriorate for several years after treatment (median time to discovery of carboplatin ototoxicity: 3.7 years), while no cases of recovery of high-grade hearing loss have been reported (Bertolini et al., 2004; Jehanne et al., 2009). These ototoxicity phenomena can have very harmful consequences for the child's social development and schooling. Oxaliplatin will be excluded from this study, as few children are currently treated with this molecule, which is generally not ototoxic.
* Detoxification of platinum derivatives The glutathione (GSH) conjugation pathway is involved in detoxification of platinum derivatives and decreases their cytotoxicity by inhibiting the formation of DNA adducts. Conjugation to GSH is ensured by glutathione-S-transferases (GSTs), which constitute a multigenic family of enzymes involved in phase II metabolism that inactivate electrophilic molecules by conjugating them to glutathione, thereby promoting their elimination. GSTP1 is particularly involved in the conjugation of platinum derivatives. Elimination of glutathione conjugates then involves membrane transporters. These conjugates can be expelled from target tumour cells and then eliminated, essentially in the urine, by efflux membrane transporters, particularly MRP2 (Sun et al., 2009). Two other enzymes, thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase, have been reported to be associated with increased toxicity of cisplatin when their activity is decreased (Ross et al., 2009).
* Genetic factors predisposing to or protecting against the toxicity of platinum derivatives Several GST isoenzymes present polymorphisms modifying their activity. This is the case for the GSTM1 and GSTT1 isoenzymes, which can undergo deletions responsible for loss of activity of the enzyme, and GSTM3, for which the GSTM3\*B allele has been associated with induction of enzyme activity by cisplatin (Peters et al., 2000). An A/G polymorphism situated in the substrate binding domain of the GSTP1 isoenzyme in position +313 of exon 5 (A313G) induces substitution of a isoleucine by a valine (Ile105Val). This polymorphism is relatively frequent (about 10% of homozygous mutants in Caucasian populations). It influences the activity of the enzyme and has been associated with better survival of patients receiving platinum-based chemotherapy (Goekkurt et al., 2006; Stoehlmacher et al., 2002; Sun et al., 2009). This polymorphism has also been shown to influence the toxicity of platinum-based treatments. For example, one study showed that the neurotoxicity of oxaliplatin was more frequent in subjects homozygous for GSTP1 105Ile allele than in heterozygous subjects or subjects homozygous for the GSTP1 105Val allele (odds ratio = 5.75). (Lecomte et al., 2006). This protective effect of the mutant allele has also been demonstrated for docetaxel peripheral neuropathies (odds ratio = 6.11) and cisplatin ototoxicity in testicular cancers in young men (Mir et al., 2009; Oldenburg et al., 2007).

A study conducted in children demonstrated an association between GSTM1 and GSTT1 polymorphisms (presence of at least one null genotype) and the development of grade 3 or higher toxicity related to treatment of medulloblastoma. However, this study, based on a small sample of children (42 children, 19 of whom experienced severe ototoxicity) and comprising patients receiving very different treatments, was unable to determine the proportion of toxicity specifically related to platinum derivatives, as some patients also received brain irradiation. Furthermore, this association between GST polymorphisms and toxicity was not observed when the analysis was specifically confined to grade 3 or higher ototoxicity. Finally, the role of GSTP1 Ile105Val polymorphism has not been evaluated in children (Barahmani et al., 2009). To our knowledge, only one study has specifically evaluated the potential impact of GST polymorphism on cisplatin ototoxicity in children. This study showed a protective effect of the GSTM3\*B variant, but did not observe a protective effect of the GSTP1 105Val allele with respect to ototoxicity, as demonstrated in adults for neurotoxicity. However, these findings were based on small sample sizes (20 patients with ototoxicity versus 19 patients without ototoxicity) and the ototoxicity experienced by these patients was grade 2 (8 patients) or 3 (12 patients) with no cases of grade 4 ototoxicity (Peters et al., 2000). The results of this study therefore need to be confirmed by a study comprising a greater number of patients, cases and controls, including patients with more severe ototoxicity. Ross et al., studying drug metabolism enzymes, demonstrated a highly significant association between cisplatin ototoxicity in children and genetic variants of TPMT (rs12201199, p = 0.00022, OR = 17.0) and COMT (rs9332377, p = 0.00018, OR = 5.5). However, as the role of these enzymes in detoxification of platinum derivatives has not been previously reported, these results need to be confirmed by other studies with, in particular, matching for age, exclusion of cases of grade 2 ototoxicity from the group of severe ototoxicity, and a greater number of control patients (Ross et al., 2009). Finally, no study has investigated the genetic factors involved in carboplatin ototoxicity in children. One study concerning membrane transporters showed that a common polymorphism situated in the promoter region of the MRP2 (-24C\>T) transporter gene was associated with a better response to platinum-based chemotherapy (allelic frequency: 18% of Caucasian) (Cascorbi, 2006; Sun et al., 2009). It would be interesting to determine whether polymorphisms affecting this gene can also modulate the toxicity of these treatments. A polymorphism of the gene coding for the influx transporter OCT2 (c.808G\>T; p.270Ala\>Ser) has also been shown to be associated in vivo and in vitro in mice with a protective effect in relation to cisplatin nephrotoxicity and ototoxicity (Ciarimboli et al.; Filipski et al., 2009), but the potential influence of this polymorphism on platinum ototoxicity has never been demonstrated in man. It therefore appears very interesting to study the potential impact of this polymorphism in the context of our study.

In summary, all of these studies clearly confirm the hypothesis that genetic factors are involved in the predisposition of some children to experience harmful ototoxic effects of platinum derivatives, particularly cisplatin and carboplatin. These studies also suggest the existence of good candidate gene variants likely to be associated with the development of this ototoxicity. However, the results of most these studies have either not been reproduced or remain controversial, indicating the need for confirmation studies based on larger sample sizes and more homogeneous patient groups in terms of treatment, as in the Otoplat study.

Cancer and Hearing Loss Related in Children

Cancer and Deafness Associated With the Use of Platinum Derivatives in Children

Assistance Publique - Hôpitaux de Paris

Infections

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Leukemia

Communicable Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Mycoses

Invasive Fungal Infections

Neutropenia

Aspergillosis

Invasive Pulmonary Aspergillosis

Pulmonary Aspergillosis

Lymphoma

Leukemia, Myeloid

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Bacterial Infections

Bacterial Infections and Mycoses

Lung Diseases

Lung Diseases, Fungal

Respiratory Tract Diseases

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Granulocytopenia

Acute Graft Versus Host Disease

Lymphosarcoma

Anti-Infective Agents

All Drugs and Chemicals

Amphotericin B

Liposomal amphotericin B

Clotrimazole

Miconazole

Antifungal Agents

Amebicides

Antiprotozoal Agents

Antiparasitic Agents

Anti-Bacterial Agents

Drug: AMPHOTERICIN B Dosage form: Abelcet® 5mg/ml administered by inhalation. Dosage: 10 ml (50 mg) for the first week with a frequency twice a week. Dosage: from the second week onwards 5 ml (25 mg) with a frequency of a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.

Duration: 4-5 prophylaxis courses defined as each administration period during a neutropenia period, with a 4-6 weeks length considering the duration of neutropenia.

The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.

AMPHOTERICIN B

Jesus Estella, PhMD

The trial evaluates the overall tolerability of the drug and the efficacy of aerosolised amphotericin B as a lipid complex (ABLC) for primary prophylaxis of invasive pulmonary aspergillosis (IPA) in pediatric patients with acute leukemia undergoing intensive chemotherapy.

In recent years the incidence of invasive fungal infection (IFI) especially when caused by filamentous fungi has increased in patients with haematological malignancies and there exists an international consensus on diagnostic criteria. Despite diagnostic and therapeutic progress, invasive aspergillosis remains a major clinical problem of haematological patients, given the still high mortality rates and the huge economic cost of hospitalization of patients, which is attributable to aspergillosis. In addition to the morbidity and mortality rates, these infections interfere with the chemotherapy treatment plan with the risk of compromising the outcome of the antileukemic treatment.

In a few uncontrolled studies inhaled amphotericin B deoxycholate showed some benefit in haematological patients, however it was not effective in a large multicenter study with neutropenic patients. Based on the outcome of that clinical trial, the use of aerosolised amphotericin B deoxycholate in neutropenic patients was abandoned for nearly a decade. During this time the use of azole agents as drugs of choice for antifungal prophylaxis in high risk patients was consolidated. However, one of the main problems in the use of triazoles with activity against filamentous fungi (itraconazole, voriconazole, posaconazole) is drug-drug interactions due to their CYP3A4 inhibitory activity. One of the most serious interactions is that which occurs with vincristine, used throughout the treatment of acute lymphoblastic leukemia, and which has lead to reports of neurotoxicity due to metabolic inhibition.

ABLC (Abelcet®) belongs to the group of polyenes with antifungal activity against a broad spectrum of fungal species, including Aspergillus spp. The active component of ABELCET®, amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. Mammalian cell membranes also contain sterols, and damage to human cells is believed to occur through the same mechanism of action.

Abelcet® is recommended for the intravenous treatment of a broad spectrum of systemic fungal infections in adult patients. Although it has a pediatric indication, there are numerous studies published regarding the safety levels of Abelcet® administered intravenously in children and in haematological adults patients which look very promising. In this context, the working hypothesis proposed in this project is that the administration of aerosolised ABLC for pediatric patients with acute leukemia treated with intensive chemotherapy will be an effective alternative as a prophylaxis of pulmonary fungal infections in these patients.

In the treatment of pediatric patients with haematological malignancies the use of intensive chemotherapy is required, which is immunosuppressive and therefore significantly increases the risk of IFI, especially filamentous fungi. IPA is associated with high mortality (\>50%) in those patients, making it imperative to adopt effective, preventive, prophylactic measures. Drug interactions occur frequently with triazole antifungal drugs; cases of clinically significant interactions with vincristine, an anchor drug in the treatment of the majority of pediatric leukemia, are documented. On the other hand, there are promising data from previous studies regarding the safety and efficacy of the intravenous ABLC formulation (Abelcet®) in the treatment of pediatric patients with fungal infections.

If the working hypothesis is confirmed, the aerosolised ABLC treatment would be an effective, safe and reliable prophylactic option for IPA. It would offer an alternative to the systemic administration of antifungal triazoles without affecting the antileukemic treatment in pediatric patients with AL.

Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia

A Phase II Trial to Evaluate the Safety and Tolerability of Nebulised Amphotericin B Lipid Complex (ABELCET®) in the Prophylaxis of Invasive Pulmonary Aspergillosis During Prolonged Neutropenia in Paediatric Patients With Acute Leukaemia

Anonymized individual data of participants will be shared with Authorities at the end of the Clinical Development Plan by the CTD (Common Technical Document). Results will be published in a scientific publication.

is assessed by the proportion of patients who discontinue prophylactic treatment with Abelcet® due to an adverse event that is related or not to the study drug or for intolerability to it. The last week of treatment will have a different calendar for each participant, depending on the number of cicles needed by each patient (it has been anticipated up to 5 cicles of 2-6 weeks each).

The incidence of invasive pulmonary aspergillosis during the Abelcet® prophylactic treatment period was assessed by the relation between the number of patients with invasive pulmonary aspergillosis and the number of paediatric patients on prophylaxis with Acute Leukaemia (AL) undergoing intensive chemotherapy.

Percentage of deaths related to Invasive Pulmonary Aspergillosis during the prophylactic treatment period with Abelcet® in paediatric patients with Acute Leukaemia undergoing intensive chemotherapy.

Ministry of Health, Spain

Fundació Sant Joan de Déu

Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).

AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.

Amphotericin B (ABELCET®)

Patients fulfilling inclusion criteria and those giving the general informed consent for the study initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).

AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization was 10 ml (50 mg) twice a week for the first week, and then from the second week onwards was reduced to 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count demonstrated to be greater than or equal to 1500 cells/mm3.

>= 3 years to <=18 years

Age, Customized

Sex: Female, Male

caucasian

amerindian

african

gypsies

patients ethnicity percentage : caucasian (84.4%), Amerindian (6.3%), African (3.1%) and gypsies (6.3%).

Race/Ethnicity, Customized

Spain

Region of Enrollment

Rosa Maria morales Palau

Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability

At baseline, none of the 32 pediatric patients with acute leukemia included in the clinical trial had API. During the trial period there were 3 patients who developed API

Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis

Invasive Pulmonary Aspergillosis -Related Mortality During Primary Prophylaxis With Abelcet®.

Overall Study

Behaviors and Mental Disorders

Neoplasms, Radiation-Induced

Quality of Life

No intervention

Neige Journy, PhD

Beate Timmermann, MD

Sofie Isebaert

Karin Haustermans

An Michiels

Sandra Jacobs

Anne Uyttebroeck

Karen Van Beek

Melissa Christiaens

Yasmin Lassen

Sanja Karabegovic

Louise Tram Henriksen

Juliette Thariat, MD

Fernand Missohou, MD

Jeanne Riverain, MD

Jordan Bouter, MD

Stéphanie Bolle

Brice Fresneau

Nadia Haddy

Valentine Martin

Martina Wette

Beate Timmermann

Stéphanie Bolle, MD

Isabelle Thierry-chef, PhD

The goal of the HARMONIC-RT study is to evaluate late health and social outcomes of contemporary techniques of external beam radiotherapy in paediatric patients, based on the setting-up of a European, long-term registry complemented by a biobank.

Specific objectives:

* To develop the infrastructure and instruments for setting-up a European, long-term registry of paediatric patients treated with contemporary techniques of modern external radiotherapy;
* To assess the incidence and severity of late health outcomes, primarily endocrine dysfunctions, cardiovascular toxicities, neurovascular damages, and subsequent primary neoplasms, in relation to the dose-volume distribution to non-targeted organs and tissues, radiation delivery technique and beam quality factors, and potential modifying factors (i.e. age at exposure, genetic predispositions, comorbidities, and systemic treatments including chemotherapy, targeted therapy, immunotherapy and hormonal drugs) that may underlie differences in individual susceptibility for these outcomes ;
* To assess societal aspects of advances in radiotherapy, primarily health-related quality of life and academic achievement, in paediatric patients treated with modern external radiotherapy techniques.

Secondary scientific objectives:

* To assess multidimensional fatigue in paediatric patients treated with modern external radiotherapy techniques, and identify clinical and therapeutic determinants of fatigue;
* To improve estimation of patient-specific doses to the whole body and non-targeted organs and substructures from different radiotherapy delivery techniques;
* To investigate radiation-induced cellular responses and biological mechanisms related to the occurrence of vascular diseases and subsequent primary neoplasms in samples of blood and saliva ; to identify biomarkers of susceptibility and health effects ; to evaluate differences in disease biomarkers in relation to the radiation delivery technique and beam quality factors ; to explore the relevance of the use of saliva as a biosampling method for paediatric cohorts regarding feasibility and the quality and reproducibility for different measured biomarkers.

Secondary strategic objectives:

* To promote sustained collaborative research activities for improvement of patient care, and inform health care providers and policy makers on the clinical and social impact of advances in radiotherapy in paediatric settings;
* To serve as a pilot for a future long-term pan-European registry of children and adolescents treated with particle and photon beam therapy, including a biobank of saliva and blood samples collected before and after treatment;
* To contribute in future collaborative projects with existing cohorts or registries in Europe
* To contribute in future international research studies on late outcomes of modern radiotherapy techniques for management of paediatric cancers

Funding: The HARMONIC project has received funding from the Euratom research and training programme 2014-2018 under grant agreement No 847707.

blood plasma; blood serum; lymphocytes; saliva

Health Effects of CArdiac FluoRoscopy and MOderN RadIotherapy in PediatriCs - Radiotherapy

Health Effects of CArdiac FluoRoscopy and MOderN RadIotherapy in PediatriCs - Radiotherapy (HARMONIC-RT)

Late health outcomes

* Neurovascular diseases
* Second and subsequent primary neaoplasms

measured as:

1. insulin-like growth factor-1,
2. anterior pituitary hormones (GH, ACTH, TSH, LH, FSH),
3. thyroid hormones (fT3, fT4),
4. sexual hormones

measured as blood markers (incl. troponin, BNP, CPK)

measured as cardiac echography parameters (incl. ejection fraction, diastolic function)

measured as scoring of large and small vessel damages

measured as signal quality of protein activity

measured as markers of oxidative stress (incl. 8-oxo-dG, SOD2, DNA repair enzymes)

Inflammatory markers (incl. PTX3, CRP, NF-kB, IL-1 and IL10)

Markers of carcinogenesis (incl. leukocyte telomere length, mitochondrial DNA copy number, circulating microRNA)

PedsQL™ multidimensional fatigue scale (validated questionnaire)

Barcelona Institute for Global Health

The West German Proton Therapy Centre, Essen

Gustave Roussy, Cancer Campus, Grand Paris

Centre Francois Baclesse

KU Leuven

University of Aarhus

Princess Maxima Center for Pediatric Oncology

University Medical Center Groningen

Stockholm University

National Research Council, Institute of Clinical Physiology, Italy

University of Zurich

Commissariat A L'energie Atomique

Luxembourg Institute of Science and Technology

University Hospital, Essen

Aarhus University Hospital

Institut National de la Santé Et de la Recherche Médicale, France

Brain Neoplasms

Medulloblastoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Hypoglycemic Agents

Metformin

Subjects assigned to this arm will receive metformin first, followed by a washout period and then placebo.

Subjects assigned to this arm will receive placebo first, followed by a washout period and then metformin.

Metformin doses will be 500 mg/m2 po daily given in 2 doses for one week and if there are no concerns increased to 1000 mg/m2 po daily given in 2 doses for the rest of the 12 week trial. The investigators will use the closest dose according to body surface area (250-500-750-1000) BID.

Placebo doses will be 500 mg/m2 po daily given in 2 doses for one week and if there are no concerns increased to 1000 mg/m2 po daily given in 2 doses for the rest of the 12 week trial. The investigators will use the closest dose according to body surface area (250-500-750-1000) BID.

Placebo

Donald Mabbott, PhD

A placebo controlled double blind crossover trial of metformin in 30 children treated with radiation for medulloblastoma - the most common malignant brain tumour. The investigators used tests of thinking and learning and brain imaging techniques to examine whether metformin can enhance cognition or promote brain repair following radiation-induced brain injury.

We conducted a pilot randomized, double-blind, placebo-controlled trial with crossover in survivors of pediatric brain tumors with primary endpoints of safety and feasibility and secondary endpoints of cognitive and magnetic resonance imaging (MRI) measures. Twenty-four participants were enrolled and randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either a group AB (AB) or group BA (BA) sequence. At the point of crossover, there was a 10-week washout period in which neither group received any treatment. During the first week of each treatment cycle, a daily dose of 500 mg/m2 of metformin or placebo was administered orally. The dose was increased to 1000mg/m2 daily beginning in the second week and continuing for the remainder of the 12-week cycle.

Test procedures (Clinical \& current medications reviews, Blood draws, and MRI and Cognitive testing) were performed at 4 times points during the study: 1. at study entry (Baseline 1), 2. after 12 weeks of treatment (Outcome 1), 3. after a 10-week washout period at 22 weeks (Baseline 2), and 4. At the end of the trial at 34 weeks (Outcome 2).

Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma

Placebo Controlled Double Blind Crossover Trial of Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma

Change in Axonal Water Fraction (AWF)- Diffusion Kurtosis Imaging (DKI) metric sensitive to myelin

Change in Hippocampal Volume, as measured by Cerebral Blood Flow (CBF)

Participant's adherence to taking study medication (Metformin or Placebo) as instructed based on dosing nomogram, for the whole study.

% Medication adherence = (Number of tablets actually consumed / Number of tablets expected to be consumed)\*100

Number of tablets actually consumed is based on compliance counts conducted at the end of the study.

The frequency of all AEs experienced during metformin and placebo treatment for all participants.

For Arm AB:

1. Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 1 (Week 13, post 12-week intervention)
2. Change in Immediate Recall test from Baseline 2 (Week 23, post 10-week washout) at Outcome 2 (Week 35, post 2nd 12-week intervention)
3. Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 2 (Week 35, post 2nd 12-week intervention)

For Arm BA:

1. Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 1 (Week 13)
2. Change in Immediate Recall test from Baseline 2 (Week 23) at Outcome 2 (Week 35)
3. Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 2 (Week 35)

For Arm AB:

1. Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 1 (Week 13)
2. Change in List Sort Working Memory Test from Baseline 2 (Week 23) at Outcome 2 (Week 35)
3. Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 2 (Week 35)

For Arm BA:

1. Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 1 (Week 13)
2. Change in List Sort Working Memory Test from Baseline 2 (Week 23) at Outcome 2 (Week 35)
3. Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 2 (Week 35)

Change in Mean Reaction Time (MRT) across the following CANTAB subtests:

1. Rapid Visual Information Processing (RVP)
2. Reaction Time (RT)
3. Match to Sample Visual Search (MTS)
4. Delayed Matching in sample (DMS)

Each subtest provides an outcome measure of response latency, which will be averaged across all correct trials for each subtest to provide an overall measure of processing speed.

For Arm AB:

1. Change in MRT from Baseline 1 (Week 1) at Outcome 1 (Week 13)
2. Change in MRT from Baseline 2 (Week 23) at Outcome 2 (Week 35)
3. Change in MRT from Baseline 1 (Week 1) at Outcome 2 (Week 35)

For Arm BA:

1. Change in MRT from Baseline 1 (Week 1) at Outcome 1 (Week 13)
2. Change in MRT from Baseline 2 (Week 23) at Outcome 2 (Week 35)
3. Change in MRT from Baseline 1 (Week 1) at Outcome 2 (Week 35)

The Hospital for Sick Children

Psychologist

Cooperative paediatric individuals and young adults (5-24-years-old) with proven Acute Lymphoblastic Leukaemia (ALL) or Acute Myeloblastic Leukaemia (AML) planned for bone marrow transplantation.

Nandita deSouza, Professor

Katherine May, BSc

This is a pilot cancer imaging study investigating change in the apparent diffusion coefficient (ADC) at a single time point post-transplantation in patients. The treatment is bone marrow transplant as per standard patient care, without change for trial purposes.

Its main aim is to evaluate the engraftment of bone marrow after transplantation performing functional Magnetic Resonance Imaging (MRI) of the lumbar spine and pelvis at baseline and after 2-3 weeks after the transplantation (according to the appearances of raised white blood cells).This will enhance the understanding of bone marrow features on imaging at engraftment and improve the management of children/young adults who suffer acute leukaemia.

Following allogenic haemopoietic stem cell transplantation, changes in bone marrow apparent diffusion coefficient (ADC) are measurable at the point of engraftment and in conjunction with peripheral blood counts may provide a future biomarker of successful clinical outcome.

This is a single-center pilot study. The investigators intend to image 12 inpatients, aged 5-24 years old who are scheduled for haemopoietic stem cell transplantation.

Patients will have two MRI scans requiring them to lie in the scanner for approximately 15 minutes. Patients unable to tolerate lying flat for this length of time or to tolerate the scan for any reason will be withdrawn from the study. If required a play specialist can be organised to help the young patients feel more at ease in the MRI department. MRI does not involve radiation exposure and when performed within national safety guidelines do not pose a significant risk. Patients with contraindications to MRI such as pacemakers, certain metal implants and claustrophobia will not be recruited. Every effort will be made to book scan appointments to coincide with clinic visits.

Scans will be reported as per clinical procedures and data will be made available to the referring consultants immediately via the radiology picture archiving and communications system (PACS).

PUMA (Paediatric Osseous Marrow Assessment)

Quantitative Magnetic Resonance Imaging of Bone Marrow in a Paediatric Population With Leukaemia (PUMA)

Measured as the percentage of children who achieve a change in ADC of their bone marrow with engraftment that is greater than the limits of agreement of repeatability of the measurement, established from previous historical data.

This will be evaluated for each patient in each scan (mean ADC for each Region Of Interest) and summarised with histograms and descriptive statistics.

A baseline magnetic resonance scan with diffusion-weighted images and without contrast administration will be performed at the end of the neoadjuvant treatment (chemotherapy with/without radiation depending on the type of leukaemia).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cancer and Hearing Loss Related in Children	NCT02425397	Cancer in Child... Hearing Loss	Genetic study Genetic study M...	4 Years -	Assistance Publique - Hôpitaux de Paris
Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia	NCT01615809	Invasive Pulmon... Lymphoblastic L... Myeloblastic Le... Lymphoblastic L... Myeloblastic Le...	AMPHOTERICIN B	3 Years - 17 Years	Fundació Sant Joan de Déu
Health Effects of CArdiac FluoRoscopy and MOderN RadIotherapy in PediatriCs - Radiotherapy	NCT04746729	Neoplasms	No intervention	- 22 Years	Institut National de la Santé Et de la Recherche Médicale, France
Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma	NCT02040376	Brain Tumor Tre...	Metformin Placebo	5 Years - 21 Years	The Hospital for Sick Children
PUMA (Paediatric Osseous Marrow Assessment)	NCT03466944	Leukaemia		5 Years - 24 Years	Institute of Cancer Research, United Kingdom
Acceptance and Commitment Therapy in Tuberous Sclerosis Complex	NCT05867576	Tuberous Sclero...	Acceptance and ...	11 Years - 24 Years	University Hospitals Bristol and Weston NHS Foundation Trust
Health Effects of CArdiac FluoRoscopy and MOderN RadIotherapy in PediatriCs - Radiotherapy	NCT04746729	Neoplasms	No intervention	- 22 Years	Institut National de la Santé Et de la Recherche Médicale, France
PUMA (Paediatric Osseous Marrow Assessment)	NCT03466944	Leukaemia		5 Years - 24 Years	Institute of Cancer Research, United Kingdom
A Post-Authorisation Safety Study Patient Registry of Patients With Neuroblastoma Being Treated With Dinutuximab Beta	NCT04253015	Neuroblastoma	Data-collection	1 Year - 18 Years	EusaPharma (UK) Limited

Spots Global Cancer Trial Database for paediatrics

Every month we try and update this database with for paediatrics cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for paediatrics

Every month we try and update this database with for paediatrics cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for paediatrics cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.