PTX3 genetically stratified randomized double-blinded allocation event-driven clinical trial for antifungal prophylaxis in patients with acute myeloid leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire Vaudois

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Decision date (initial)

2024-10-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Swiss National Science Fondation grant 33IC30 179636

External identifiers

EU CT number

2024-517211-79-00

EudraCT number

2019-001585-15

ClinicalTrials.gov

NCT03828773

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis

The main objective is to demonstrate that, in the high risk strata, the probability of experiencing proven and probable invasive mold infections during the treatment period (days 0-180) in AML/MDSit patients treated with posaconazole is lower than in patients treated with fluconazole, i.e the absolute risk reduction (ARR) is greater than 0.

Secondary objectives 4

1. To determine whether in the low risk strata, the probability of experiencing proven and probable IMI* during the treatment period (days 0-180) in patients treated with posaconazole is lower than in patients treated with fluconazole (ARR > 0).
2. To compare the absolute risk reduction (ARR) obtained by the use of posaconazole versus fluconazole prophylaxis on the cumulative incidence of proven and probable IMI in AML/MDSit patients between high risk strata and low risk strata. Accordingly compare the number of patients needed-to-treat (NNT being the inverse of ARR) between high risk and low risk strata.
3. To identify whether the risk reduction of experiencing proven and probable IMI between posaconazole versus fluconazole prophylaxis differs between genetically risk-stratified groups, i.e. whether the hazard ratio is dependent on PTX3 SNPs.
4. To evaluate the above objectives (primary and secondary) on secondary outcomes.

Conditions and MedDRA coding

Antifungal prophylaxis in patients with acute myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Signed informed consent according to national/local regulations
2. Age ≥18 years
3. Diagnosis of AML or MDSit (de novo or secondary) treated with an intensive chemotherapy regimen, including induction / consolidation / salvage chemotherapy
4. Planned hospital admission for the duration of the neutropenic phase (ANC<500 cells/mm3)

Exclusion criteria 12

1. Patients with neutropenia (ANC<500 cells/mm3) at hospital admission (first inpatient blood analysis)
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 IFI within 3 months prior to study enrolment and an 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: AST, ALT, alkaline phosphatase, and/or total bilirubin above >5x upper limit of normality documented on the first inpatient analysis if still present at inclusion and considered contra-indicated by the clinical team
7. Patients with a prolonged QTc interval on at least 2 electrocardiograms (ECG): QTc greater than 450 msec for men and greater than 470 msec for women, and if considered contra-indicated by the clinical team
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 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The cumulative incidence of proven and probable invasive fungal infections, invasive mold infections and invasive aspergillosis (IMI) at 180 days is defined as the proportion of patients who experienced proven and probable IMI within 180 days from the first dose of antifungal prophylaxis treatment after randomization.

Secondary endpoints 7

1. The cumulative incidence of possible IMI by day 180 in the ITT population.
2. The cumulative incidence of probable and proven IFI, namely: (a) all IFI, (b) IA only and (c) IC only in the ITT patient population by day 180
3. The time to probable and proven IMI during 180 days in the ITT population.
4. The overall survival in the ITT population by day 180.
5. The time to first use and the number of patient-days of amphotericin B or an echinocandin in the ITT population during 180 days.
6. The frequency and distribution of adverse events (AE) of interest in posaconazole and fluconazole treated participants in the ITT population during 180 days, namely (a) elevation of liver tests and (b) prolongation of QTc interval on ECG.
7. The cumulative incidence of probable and proven IFI, namely: all IFI, all IMI, IA only and IC only in the per protocol (PP) population by day 180.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire Vaudois

Sponsor organisation

Centre Hospitalier Universitaire Vaudois

Address

Rue Du Bugnon 19/04

City

Lausanne

Postcode

1005

Country

Switzerland

Scientific contact point

Organisation

Centre Hospitalier Universitaire Vaudois

Contact name

Prof. Pierre-Yves Bochud

Public contact point

Organisation

Centre Hospitalier Universitaire Vaudois

Contact name

Prof. Pierre-Yves Bochud

Locations

2 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications