Study on genetic allocation of antifungal prophylaxis in patients treated for acute myeloid leukemia
Descrizione riassuntiva dello studio
The aim of this study is to determine to what extent a genetic test of PTX3 allows for optimizing the choice of antifungal prophylaxis in terms of individual risks and benefits. This is an international study aiming to include 320 patients over a period of 3.5 years. The duration of the study for each participant is 6 months. Once the PTX3 genetic test is performed (from a blood sample) and as soon as the number of white blood cells decreases, the patient will receive either a “narrow-spectrum” or “broad-spectrum” prophylaxis selected by randomization. At the end of the study, the frequency of fungal infections and adverse effects due to antifungals will be compared for each patient group according to their risk level (high or low) and according to the type of prophylaxis.
(BASEC)
Intervento studiato
Prophylaxis will be assigned to the patient based on randomization, either:
A) Fluconazole (narrow-spectrum prophylaxis)
B) Posaconazole (broad-spectrum prophylaxis)
For statistical reasons and to minimize exposure to broad prophylaxis in low-risk subjects, 1 in 2 patients in the high-risk group will receive posaconazole and 1 in 2 will receive fluconazole. In contrast, the randomization ratio will favor narrow-spectrum prophylaxis in the low-risk group (3 out of 4 patients will receive fluconazole, 1 out of 4 will receive posaconazole). Prophylaxis will be initiated as soon as the white blood cell count falls below a predefined threshold value (day 0).
In case of side effects or ineffectiveness, dosage modifications, a change of prophylaxis, or discontinuation of prophylaxis may be decided at any time by the physician managing the patient, as is usually done in clinical routine.
(BASEC)
Malattie studiate
Patients treated with intensive chemotherapy for leukemia are at risk of developing fungal infections due to the transient decrease in white blood cell count. These infections can be prevented by the preventive administration of antifungal medications (prophylaxis). For several years, a fluconazole prophylaxis has been administered in most hematology departments as a routine measure for the prevention of fungal infections; fluconazole primarily prevents fungal infections known as candidiasis (narrow-spectrum prophylaxis), and this with lower risk, as the drug is generally well tolerated. More recently, posaconazole has been increasingly used instead of fluconazole for antifungal prophylaxis in high-risk patients; posaconazole has the advantage of preventing a greater number of fungal infections, including aspergillosis (and similar infections) in addition to candidiasis (broad-spectrum prophylaxis). However, the benefit of this approach is counterbalanced by adverse effects and more frequent interactions with other medications and by the emergence of resistant fungi (difficult to treat). These factors should be considered especially since the risk associated with aspergillosis (and similar infections) is relatively limited in many hospital services, due to a relatively low infection rate and/or preventive and monitoring measures allowing for quicker detection and more effective treatment than in the past. Approximately 20-30% of individuals carry a variant of an immune system gene called “long pentraxin 3” (PTX3). This variant confers an increased risk of developing fungal infections (aspergillosis) that are not prevented by usual prophylaxis (narrow-spectrum), but by broad-spectrum prophylaxis.
(BASEC)
1. Patients aged 18 years and older who have signed the informed consent for the study 2. Patients who will benefit from intensive chemotherapy for the treatment of acute myeloid leukemia or a similar disease 3. Planned hospitalization during the neutropenia phase (absolute neutrophil count <500/mm3) (BASEC)
Criteri di esclusione
1. Patients with neutropenia (absolute neutrophil count <500/mm3) before the start of chemotherapy 2. Patients with promyelocytic leukemia 3. Any contraindication to treatment with azole antifungals. (BASEC)
Luogo dello studio
Aarau, Basilea, Friburgo, Ginevra, Losanna
(BASEC)
Sponsor
CHUV, Lausanne
(BASEC)
Contatto per ulteriori informazioni sullo studio
Persona di contatto in Svizzera
Prof. Pierre-Yves Bochud
+41 21 314 43 79
Pierre-Yves.Bochud@clutterchuv.chCHUV
(BASEC)
Informazioni generali
Centre Hospitalier Universitaire Vaudois,
0041 213144379
Pierre-Yves.Bochud@clutterchuv.ch(ICTRP)
Informazioni generali
Centre Hospitalier Universitaire Vaudois
0041 213144379
Pierre-Yves.Bochud@clutterchuv.ch(ICTRP)
Informazioni scientifiche
Centre Hospitalier Universitaire Vaudois,
0041 213144379
Pierre-Yves.Bochud@clutterchuv.ch(ICTRP)
Nome del comitato etico approvante (per studi multicentrici solo il comitato principale)
Commissione d'etica Vaud
(BASEC)
Data di approvazione del comitato etico
09.11.2018
(BASEC)
ID di studio ICTRP
NCT03828773 (ICTRP)
Titolo ufficiale (approvato dal comitato etico)
PTX3 genetically stratified randomized double-blinded allocation event-driven clinical trial for antifungal prophylaxis in patients with acute myeloid leukemia (BASEC)
Titolo accademico
PTX3 Genetically Stratified Randomized Double-blinded Allocation Event-driven Clinical Trial for Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia (ICTRP)
Titolo pubblico
PTX3-targeted Antifungal Prophylaxis (ICTRP)
Malattie studiate
CandidiasisFungal InfectionAcute Myeloid LeukemiaGenetic PredispositionAspergillosis (ICTRP)
Intervento studiato
Drug: PosaconazoleDrug: Fluconazole (ICTRP)
Tipo di studio
Interventional (ICTRP)
Disegno dello studio
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Prevention. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor). (ICTRP)
Criteri di inclusione/esclusione
Inclusion Criteria:
1. Signed Informed Consent according to national/local regulations.
2. Age =18 years.
3. Diagnosis of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome in
transformation (MDSit) treated with an intensive chemotherapy regimen, including
induction / consolidation / salvage remission chemotherapy.
4. Planned hospital admission for the duration of the neutropenic phase (absolute
neutrophils count <500 cells/mm3).
Exclusion Criteria:
1. Patients with neutropenia (absolute neutrophils count<500 cells/mm3) upon
presentation and prior to chemotherapy initiation.
2. Patients with a diagnosis of acute promyelocytic leukemia (APL) or AML-M3.
3. Patients with known history of allergy, hypersensitivity or serious reaction to
azole antifungals
4. Women who are pregnant (positive blood/urine pregnancy test within 10 days before
randomization) or breast-feeding.
5. Diagnosis and treatment for an Invasive Fungal Infection (IFI) within 3 months prior
to study enrolment and an Invasive Mold Infection (IMI) at any point prior to or at
the time of enrolment.
6. Severe liver dysfunction, defined as at least one of the following markers:
Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) or alkaline
phosphatase above >5x upper limit of normality: and/or total bilirubin above >3x
upper limit of normality.
7. Patients with an ECG with a prolonged QTc interval: QTc greater than 450 msec for
men and greater than 470 msec for women.
8. Patients who are receiving and cannot discontinue the following drugs at least 24
hours prior to randomization: terfenadine, astemizole, cisapride, pimozide,
halofantrine or quinidine (because of the possibility of QT prolongation),
sirolimus, rifampin, rifabutin, carbamazepine, long-acting barbiturates (e.g.,
phenobarbital, mephobarbital), ritonavir, efavirenz, or ergot alkaloids (e.g.,
ergotamine, dihydroergotamine).
9. Serious uncontrolled concomitant disease or comorbidity that, in the opinion of the
investigator, may compromise adherence to the study protocol.
10. Receipt of a prior allogeneic Hematopoietic Cell Transplantation (HCT).
11. Previous exposure to mold-active prophylaxis (>48 hours within 7 days of inclusion).
12. Patients with relapsed leukemia already included in the trial.
13. Patient not affiliated to the French social security system
14. Patient under legal protection (guardianship, curatorship) (ICTRP)
non disponibile
Endpoint primari e secondari
Cumulative incidence of proven and probable invasive mold infection (IMI) (ICTRP)
Cumulative incidence of possible invasive mold infection (IMI);Cumulative incidence of probable and proven Invasive Fungal Infections (IFI);Time to probable and proven invasive mold infection (IMI);Cumulative incidence of mortality;Time to first use and number of patient-days of amphotericin B/echinocandin;Frequency/distribution of adverse events (AE) of interest;Treatment success versus failure;Cumulative incidence of probable and proven invasive fungal infections (IFI) in per protocol population (ICTRP)
Data di registrazione
non disponibile
Inclusione del primo partecipante
non disponibile
Sponsor secondari
Swiss National Science Foundation (ICTRP)
Contatti aggiuntivi
Pierre-Yves Bochud, MD;Pierre-Yves Bochud, MD, Pierre-Yves.Bochud@chuv.ch, 0041 213144379, Centre Hospitalier Universitaire Vaudois, (ICTRP)
ID secondari
2018-01671 (ICTRP)
Risultati-Dati individuali dei partecipanti
non disponibile
Ulteriori informazioni sullo studio
https://clinicaltrials.gov/study/NCT03828773 (ICTRP)
Risultati dello studio
Riepilogo dei risultati
non disponibile
Link ai risultati nel registro primario
non disponibile