Substance Related Disorders

All Conditions

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Collection of adverse drug events

01 Studienregister MasterAdmins

The proposed cohort study collected within a 5-month observation period adverse drug reaction (Adverse Drug Events - ADE) in patients at the Department of Oncology at the University of Zurich. ADE have been recorded using prospective monitoring and assessed using standardized algorithms regarding causality and severity. Data sources included information from the medical records, laboratory values and internal rounds. Additional information has been collected using a standardized patient questionnaire.

The primary endpoints of this study are to determine the frequency of ADE, the comparison of the quality of data sources and collection methods for the detection of ADE in regard to patient characteristics, size, number of medications, the category of ADE, severity, causation, diagnosis, hospitalization, cause of hospitalization and medication cause. Secondary endpoint is the assessment of the ADE causality, severity and predictability.

Collection, Evaluation and Assessment of Adverse Drug Reactions on the Oncology Ward

University of Zurich

Blood and Lymph Conditions

Hematologic Diseases

Cases reported in the World Health Organization (WHO) and the French pharmacovigilance database of patients treated by Chimeric Antigen Receptor T-cell and Cellular Therapies, with a chronology compatible with the drug toxicity

Chimeric Antigen Receptor T-cell and Cellular Therapies for the treatment of a cancer either solid or hematologic malignancy

CAR T-cell and Cellular Therapies

CAR-T cells and cellular therapies may lead to various adverse reactions. This study investigates reports of different toxicities for cellular therapies in the World Health Organization's (WHO) global database of individual safety case reports (VigiBase).

CAR-T cells and cellular therapies are responsible of a wide range of side effects.The investigators use VigiBase, the World Health Organization (WHO) database of individual safety case reports, to identify cases of adverse drug reactions following treatment with cellular therapies

Chimeric Antigen Receptor T-cell and Cellular Therapies for the Treatment of cAncer or BLood Diseases: Evaluation of Reporting of Adverse Events

Identification and report of various toxicities of cellular therapies.

Groupe Hospitalier Pitie-Salpetriere

Principal Investigator

Neoplasms

Infections

Rare Diseases

Hematologic Neoplasms

Aspergillosis

Anti-Infective Agents

All Drugs and Chemicals

Voriconazole

Clotrimazole

Miconazole

Antifungal Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

All eligible patients will be followed up for voriconazole related adverse drug events and efficacy

This is an observational study and only the patients already on voriconazole treatment will be included in the study.

Mukaddes Gumustekin, Professor, MD, PhD

Ozge Akcay, MD

Hale Oren, Professor, MD

Sebnem Yilmaz, Professor, MD

Nursen Belet, Professor, MD

Deniz Yilmaz Karapinar, Professor, MD

Bucak Tatli Gunes, MD

Ayfer Ulgenalp, Professor, PhD

Altug Koc, MD, PhD

Muharrem Anil Gurkan, MD

Mert Sarilar, MD

Richard Myles Turner, MD, PhD

Munir Pirmohamed, Professor, MD, PhD

Voriconazole is a drug used to treat invasive fungal infections. The amount of voriconazole in a person's blood helps to determine how effectively it treats an infection, and how safe it is. Patients respond differently when receiving the same dose - some clearly benefit, other patients experience side effects, and others see limited improvement in their infection.

Voriconazole is broken down in the liver mainly by an enzyme called CYP2C19, before being excreted from the body. The activity of CY2C19 differs between people because of variation in the DNA that encodes the body's instructions to make CYP2C19.

If CYP2C19 activity is very high, voriconazole blood levels may remain below the target range when a patient receives a standard dose of voriconazole, which may be insufficient to treat their infection. Besides, children tend to have faster voriconazole metabolism regardless of the genetic makeup, mainly because of higher liver mass/body proportion. That's why, younger patients needs higher doses and it is harder for them to reach target range. Having a high CYP2C19 activity and being young combined may cause to consider choosing an alternative drug. By contrast, decreased CYP2C19 activity due to genetic variation may result in excessively high voriconazole blood levels, predisposing to serious side effects.

Therefore, knowing a patient's CYP2C19 genetic makeup is very important for predicting their response to voriconazole.

Thus, we aim to determine the influence of genetic variation in CYP2C19 on the frequency and severity of side effects related to voriconazole, and on the effectiveness of voriconazole for treating serious fungal infections. The findings from this study will contribute to determining the optimal dose of voriconazole that patients with different genetic variants in CYP2C19 should be started on, and will take us one step closer to both understanding the genetic structure of CYP2C19 in the Turkish population, and to 'personalised medicine'.

Invasive fungal infections are the leading cause of mortality and morbidity in immune compromised children. Aspergillus species are reported to be the most common molds that cause invasive infections among pediatric patients both in the United States and in Europe.

Voriconazole is recommended as the first line therapy for invasive Aspergillosis. The major proportion of the drug undergoes hepatic metabolism via cytochrome enzymes. The hepatic cytochrome enzyme that mainly involves in the metabolism of voriconazole is CYP2C19, which is known to be highly polymorphic. So far, more than 30 variant alleles have been defined in the gene that codes CYP2C19 enzyme.

Polymorphisms in CYP2C19 gene are associated with alterations in voriconazole metabolism. It is postulated that only 35-50% of the populations has normal metabolic activity for this drug. The carriers of defective alleles (\*2/\*2, \*2/\*3, \*3/\*3) in CYP2C19 gene have slower metabolic activity for voriconazole, while the carriers of \*17 allele have increased enzyme activity and higher metabolic capacity for the drug.

Voriconazole has a narrow therapeutic window. When the therapy is initiated with standard doses, interpersonal differences in CYP2C19 activity make it difficult to remain in the optimal therapeutic range. Furthermore, it is reported that voriconazole concentrations in pediatric patients can exhibit up to 3-fold variation among individuals and it is extremely hard to reach and remain therapeutic concentration in younger children. As low serum concentrations cause decreased efficacy, supratherapeutic concentrations may cause voriconazole toxicity which also leads to significant morbidity, mortality and high treatment costs.

To ensure desired efficacy and safety of voriconazole treatment, therapeutic drug monitoring (TDM) is recommended, but unfortunately, it is not a part of routine clinical care in many hospitals, due to frequent blood sampling and analysis requirements and the high analysis costs. On the other hand, starting the therapy with standard doses and adjusting it with subsequent TDMs may cause delay in selecting optimal voriconazole dose and providing effective treatment.

It is reported that, pediatric patients those are initiated voriconazole therapy with pharmacogenetic-guided dose selection reaches targeted serum voriconazole concentration 4-fold faster than the patients those are given standard doses and undergoes subsequent dose adjustments according to TDM results. Thus, CYP2C19 genotyping is essential in reaching the optimal voriconazole concentration in shorter times. Genotype-guided first dose selection would make it easier to reach the targeted serum voriconazole concentration, minimize frequent TDM requirement, prevent the treatment failure and lead to better clinical outcomes. On the other hand, pharmacogenetic analysis results can also be used for adjusting dose of other drugs that is metabolized by the same enzyme.

We could only located one conference proceeding reporting the effect of CYP2C19 polymorphisms on safety of voriconazole use in 6 patients in Turkish population. Current literature is limited and the guidelines does not make a clear recommendation about the pharmacogenetic-guided dose selections. Thus, to build safe pharmacogenetic- guided dose selection algorithms, more data in that field is required.

This study is designed to prospectively determine the influence of CYP2C19 polymorphisms on frequency and severity of voriconazole related adverse event reactions during the study follow up period and on the efficacy of voriconazole treatment/ prophylaxis. Samples for pharmacogenetic analysis will be stored for further studies depending on participant's and the parents' discreation.

METHOD This is a multi centre, observational cohort study.

Study population:

Patients aged between ≥2 years and \<18 years hospitalized in pediatric hematology clinics in research centers (Dokuz Eylul University Hospital, Ege University Hospital, Izmir University of Health Sciences Tepecik Training and Research Hospital) due to a hematological malignancy (acute lymphoblastic leukemia, acute myeloid leukemia) and receiving voriconazole as part of invasive fungal infection prophylaxis or treatment.

Data and sample collection 1.1.1.Data collection: At baseline, demographics and clinical information will be recorded from all patients directly and complemented from their medical records. All patients will be followed up by the research team daily for the first 7 days following voriconazole initiation, and then on days 14, 30 and 60. All follow up will be initially via assessment of medical records, with additional data input from the patient directly. The medical records include: the electronic hospital record system (PROBEL), paper-based patient records and other patient follow-up- documents.

During routine clinical care, ADRs are monitored daily by a pediatric hematology fellow and/or pediatrician. On days one to seven following voriconazole initiation, the investigators will record these clinical evaluations daily; they will also capture these data on days 14 and 30.

For participants that had either started voriconazole active treatment before they were recruited, or were recruited during the maintenance phase of their voriconazole regimen, the research team will assess their medicals records retrospectively between the point of recruitment and day one of their active voriconazole treatment to detect ADRs.

On days 30 and 60, patient survival will be recorded by review of patient records only.

Treatment response (efficacy) will be determined based on the EORTC/MSG consensus criteria. These data will be obtained at all follow up points (from day one to seven, and days 14, 30 and 60).

1.1.2.Sample collection: 1.1.2.1.Samples fo PGx analysis: All pediatric patients with a hematologic malignancy (acute lymphoblastic leukemia, acute myeloid leukemia) hospitalized aforementioned study centers and their parents will be informed of the study. Those agree to participate in will donate 2 mL blood sample collected into an EDTA (Ethylenediaminetetraacetic Acid) tube on day one whilst blood samples are being taken from the patient for daily routine clinical purposes (without requiring any other needle insertion). Samples for PGx analysis will be coded and stored securely in Dokuz Eylul University Hospital, Department of Medical Pharmacology. The samples will be stored -80 celcius degree until used up. PGx analysis will be performed in the Department of Medical Genetics at Dokuz Eylul University Hospital at the end of the study. Participants and physicians will not be informed of the participant's genotype during the study period. The participant's clinical care will not be affected in any way by taking part in the study.

1.1.2.2.Samples for voriconazole concentration determination: The patients those start using voriconazole as part of invasive fungal infection prophylaxis or treatment will The second 2 mL blood sample will be collected into a red cap tube on the fifth day (9th dose) of treatment before the morning voriconazole dose, again whilst blood is being collected as part of routine clinical care (without requiring any other needle insertion) to determine the trough voriconazole concentration at steady state. This blood sample will be centrifuged and the serum stored in the Department of Medical Pharmacology at the Dokuz Eylul University Faculty of Medicine. When follow up is completed for a given patient, this serum sample will be transferred to an accredited laboratory in Istanbul, Turkey, with maintenance and assurance of the cold chain during sample transportation to guarantee sample integrity.

2 mL of blood sample collected into an EDTA (Ethylenediaminetetraacetic Acid) tube for PGx analysis and another 2 mL of blood sample collected into an EDTA (Ethylenediaminetetraacetic Acid) tube for voriconazole TDM

Influence of CYP2C19 Genotype on Safety and Efficacy of Voriconazole in Pediatric Patients With Hematologic Malignancy

Voriconazole related adverse drug reactions of grade 3-5 systematically evaluated using Liverpool Causality Assessment Tool identified during study follow up.

Severity of all adverse events will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

The efficacy of voriconazole treatment will be assessed based on reviews of clinical, mycological and radiological data according to the Mycoses Study Group and European Organization for Research and Treatment of Cancer Consensus Criteria (EORTC/MSG criteria).

Voriconazole trough concentration will be measured once for each participant from plasma samples collected 30 minutes before the 9th dose of voriconazole

Patient survival will be evaluated on days 30 and 60 by reference to the Dokuz Eylul University Hospital Hematology Service; date of death will be captured to permit survival analysis.

University of Liverpool

Dokuz Eylul University

Full Professor

Heart and Blood Diseases

Nutritional and Metabolic Diseases

Symptoms and General Pathology

Wounds and Injuries

Heart Failure

Vascular Diseases

Metabolic Diseases

Heart Diseases

Cardiotoxicity

Radiation Injuries

Drugs and treatments used in cancer inducing cardiovascular and metabolic side effects

Anti-Cancer Agents

Joe-Elie Salem, MD, PhD

Stéphane Edehry, MD

Edehry Stephane, MD

Joe-Elie Salem, Md, PhD

Several Drugs used in routine care in oncology induce rare but often severe or fatal cardiovascular or metabolic side effects. This study will investigate, evaluate, report and treat the cardiovascular side effects of anticancer drugs, through a specific cardiovascular routine checkup and follow-up taking place in several Cardio-oncology programs throughout France. The different including centers will be: Assistance Publique - Hôpitaux de Paris (APHP.6: Pitié-Salpétrière, Saint Antoine and Tenon's hospitals, Paris, France).

Several anticancer and supportive care drugs used in oncology have an impact on the cardiovascular and metabolic systems, leading to a wide range of cardiovascular and metabolic disorders and side effects. Those are poorly described, due to the evolution of the anticancer pharmacopeia, and recent recognition of these adverse events. This study will investigate the potential benefits of a specialized cardio-oncology check-up and follow-up in this context.

Reporting, Evaluating, Preventing and Treating the Cardiotoxicity Induced by Anticancer Drugs During a Specific Cardio-oncology Consult and Follow up in Routine Care

Assistant director, clinical investigation center Paris Est

Immune System Diseases

Recurrence

Lymphoma

Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

Lymphoma, T-Cell, Cutaneous

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Peripheral T-cell Lymphoma

Cutaneous T-cell Lymphoma

Antineoplastic Agents

Denileukin diftitox

Participants with recurrent or refractory peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL) will be administered with Remitoro 9 microgram per kilogram (mcg/kg), intravenous (IV) infusion, over 1 hour once daily for 5 consecutive days followed by 16 days withdrawal period in a 21 day cycle (up to maximum of 8 cycles). The dosage will be adjusted depending on the condition of the participant. All the participants will be observed for up to 24 weeks prospectively.

Remitoro

The primary purpose of the study is to investigate the incidence of adverse drug reactions (ADRs) (ADR of special interest: capillary leak syndrome, infusion reaction, rhabdomyolysis, myelosuppression, infection, hepatic dysfunction, visual impairment/color blindness, ischemic heart disease/arrhythmia/cardiac failure, and severe skin disorders).

A Study of Remitoro in Participants With Recurrent or Refractory Peripheral T Cell Lymphoma and Cutaneous T Cell Lymphoma (All Case Study)

Post-marketing Observational Study of Remitoro® Intravenous Injection 300 μg - Safety of Remitoro in Patients With Recurrent or Refractory Peripheral T Cell Lymphoma and Cutaneous T Cell Lymphoma (All Case Study)

Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

Incidence of ADR, especially for capillary leak syndrome, infusion reaction, rhabdomyolysis, myelosuppression, infection, hepatic dysfunction, visual impairment/color blindness, ischemic heart disease/arrhythmia/cardiac failure, and severe skin disorders will be assessed. An ADR is defined as harmful and unintended responses to the normal administration/use of drugs, in which a causal relationship with the drug in question cannot be ruled.

Percentage of participants with a best overall response of complete response (CR) or partial response (PR) based on physician assessment will be determined. PTCL is evaluated according to revised response criteria for malignant lymphoma (Cheson, 2007). CTCL is evaluated according to clinical endpoints and response criteria in mycosis fungoides and sezary syndrome (Olsen, 2011). CR: Disappearance of all evidence of disease; PR: Regression of measurable disease and no new sites.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Collection, Evaluation and Assessment of Adverse Drug Reactions on the Oncology Ward	NCT01058122	Adverse Drug Re...	Collection of a...	18 Years -	University of Zurich
Chimeric Antigen Receptor T-cell and Cellular Therapies for the Treatment of cAncer or BLood Diseases: Evaluation of Reporting of Adverse Events	NCT04279470	Adverse Drug Re... Cancer	CAR T-cell and ...	- 100 Years	Groupe Hospitalier Pitie-Salpetriere
Collection, Evaluation and Assessment of Adverse Drug Reactions on the Oncology Ward	NCT01058122	Adverse Drug Re...	Collection of a...	18 Years -	University of Zurich
Chimeric Antigen Receptor T-cell and Cellular Therapies for the Treatment of cAncer or BLood Diseases: Evaluation of Reporting of Adverse Events	NCT04279470	Adverse Drug Re... Cancer	CAR T-cell and ...	- 100 Years	Groupe Hospitalier Pitie-Salpetriere
Influence of CYP2C19 Genotype on Safety and Efficacy of Voriconazole in Pediatric Patients With Hematologic Malignancy	NCT04743544	Adverse Drug Re...	Voriconazole	2 Years - 18 Years	Dokuz Eylul University
Reporting, Evaluating, Preventing and Treating the Cardiotoxicity Induced by Anticancer Drugs During a Specific Cardio-oncology Consult and Follow up in Routine Care	NCT03882580	Cardiovascular ... Cardiovascular ... Cardiac Complic... Oncologic Compl... Cardiac Insuffi... Metabolic Disor... Vascular Disord... Cardiac Disorde...	Anti-Cancer Age...	18 Years -	Groupe Hospitalier Pitie-Salpetriere
A Study of Remitoro in Participants With Recurrent or Refractory Peripheral T Cell Lymphoma and Cutaneous T Cell Lymphoma (All Case Study)	NCT05137847	Lymphoma, T-cel... Lymphoma, T-cel...	Remitoro	-	Eisai Inc.
Influence of CYP2C19 Genotype on Safety and Efficacy of Voriconazole in Pediatric Patients With Hematologic Malignancy	NCT04743544	Adverse Drug Re...	Voriconazole	2 Years - 18 Years	Dokuz Eylul University
Reporting, Evaluating, Preventing and Treating the Cardiotoxicity Induced by Anticancer Drugs During a Specific Cardio-oncology Consult and Follow up in Routine Care	NCT03882580	Cardiovascular ... Cardiovascular ... Cardiac Complic... Oncologic Compl... Cardiac Insuffi... Metabolic Disor... Vascular Disord... Cardiac Disorde...	Anti-Cancer Age...	18 Years -	Groupe Hospitalier Pitie-Salpetriere

Spots Global Cancer Trial Database for adverse drug reactions