Primary objective 1. Evaluate if the survival in patients with a triazole susceptible IA can be improved when the initial therapy consists of triazole and echinocandin combination therapy instead of triazole monotherapy. (This objective is captured…
ID
Source
Brief title
Condition
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall survival 6 weeks after the start of antifungal therapy in the MITT
population
Secondary outcome
1. Overall survival 6 weeks after the start of antifungal therapy in the ITT
population
2. Overall aspergillus attributable mortality 12 weeks after the start of
antifungal therapy.
3. Overall survival 12 weeks after the start of antifungal therapy in the MITT
population
4. Overall survival 6 weeks after the start of therapy in the subgroup of
patients in the MITT population with a positive serum galactomannan test at
baseline.
5. Overall survival 6 weeks after the start of therapy in the subgroup of
non-ICU patients who fulfill the EORTC/MSG probable or proven definition (MITT
population).
6. Overall survival 6 weeks after the start of therapy in the subgroup of
non-ICU patients with an underlying haematological disease (MITT population)
7. Overall survival 6 weeks after the start of therapy in the subgroup of
non-ICU patients without an underlying haematological disease (MITT population)
8. Overall survival 6 weeks after the start of therapy in patients that started
with triazole monotherapy and in which triazole resistance is detected during
follow-up
9. Overall survival 6 weeks after the start of therapy in patients that started
with triazole-anidulafungin combination therapy and in which triazole
resistance is detected during follow-up
10. In the subgroup of patients with a positive serum galactomannan; Kinetics
of serum galactomannan levels with combination versus monotherapy
11. Outcome of patients in which resistance testing was unsuccessful
12. Time to hospital discharge (in the MITT subgroup of patients admitted to
the hospital at baseline)
13. Time to hospital discharge (in the ITT subgriup of patients admitted to
the hospital at baseline)
14. Cost-effectivity of azole-anidulafungin combination therapy
Background summary
Patients with underlying haematological malignancies or immunocompromised for
various other reasons, are prone to fungal infections. Invasive aspergillosis
(IA) is a common complication during remission inducing chemotherapy for acute
leukemia or other hematological malignancies, as well as those who have
undergone allogeneic hematopoietic stem cell transplantation (HSCT) or solid
organ transplantation (SOT). For more than 15 years voriconazole, a drug of the
triazole class, has been the recommended treatment for this life-threatening
infection after a pivotal randomized trial showed an improved survival with
voriconazole compared with amphotericin B deoxycholate. However, also with
voriconazole the overall 6-week mortality is still unacceptably high at 25-30%
(Herbrecht et al., 20021). Therefore, a randomized controlled trial assed the
efficacy of voriconazole with or without anidulafungin for the treatment of IA
in haematology patients to prove that combination therapy can improve outcome.2
Among the 277 patients with IA in this study, the 6-week mortality with
combination therapy was 30% lower (19.3%) than with monotherapy (27.5%),
p=0.087. In a post-hoc analysis of the 222 patients with radiographic
abnormalities and a positive galactomannan antigen test, a statistically
significant difference in mortality was observed (p=0.037). Though, this study
did not result in conclusive evidence in favor of combination therapy, it is a
credible study which adds to the already existing in vitro and animal studies
in support of echinocandin triazole combination therapy for IA and thus paves
the way for a second larger and pragmatic clinical trial. Another important and
new consideration about the management of IA is the upcoming of infections with
triazole-resistant A.fumigatus. This is increasingly becoming a worldwide
problem and leads to longer hospital stay, higher costs and is associated with
a very high mortality. It is very likely that the excessive use of antifungals
of the triazole class in agriculture has formed the basis of this problem.
Since 2018 the Dutch Working Party on Antibiotic therapy (SWAB) guideline on
the management of invasive fungal infections therefore recommends upfront
combination therapy (azole plus echinocandins or liposomal-amfotericine B)
until resistance can be excluded as one of the treatment options for IA.
Given the evidence in favor of voriconazole-echinocandin combination therapy as
well as the increasing incidence of voriconazole-resistant A. fumigatus in
Belgium and the Netherlands, a large clinical study on the value of combination
therapy is urgently needed.
Study objective
Primary objective
1. Evaluate if the survival in patients with a triazole susceptible IA can be
improved when the initial therapy consists of triazole and echinocandin
combination therapy instead of triazole monotherapy. (This objective is
captured in the primary endpoint as well as secondary endpoints 2 to 7)
Secondary objectives
1. Evaluate if the survival in patients with an IA in whom azole resistance
was not detected can be improved by starting triazole/echinocandin combination
therapy compared to the local standard of care. This IA study population
includes patients in whom resistance testing was successful and resistance was
not detected OR patients in whom resistance testing was unsuccessful. This
objective is captured in the first secondary endpoint..
2. Evaluate if a triazole/echinocandin combination therapy improves the overall
quality of life and if it is a cost-effective intervention (these objectives
are captured in secondary endpoint 12, 13 and 14)
23. Evaluate the outcome of patients in which a triazole-resistant A.
fumigatus is detected in relation to the initial antifungal therapy they had
received (i.e. triazole monotherapy or combination therapy). This objective
translates into secondary endpoint 8 an 9.
43. Evaluate the outcome of patients in which resistance testing is
unsuccessful in function of the antifungal therapy they received. This
translates into secondary endpoint 11.
45. Evaluate if the baseline serum galactomannan value and the serum
galactomannan kinetics are predictive of overall 6-week survival. This
translates into secondary endpoint 4 and 10.
Study design
A non-blinded phase 3 randomized pragmatic clinical trial.
Intervention
Intervention:
Treatment with a triazole (voriconazole or isavuconazole or posaconazole) +
anidulafungin IV. The triazole is administered for at least 6 weeks while
anidulafungin is given for at least 7 and a maximum of 28 days.
Comparator:
Treatment with a triazole (voriconazole or isavuconazole or posaconazole) for
at least 6 weeks.
Study burden and risks
The safety of this combination therapy has previously been demonstrated in a
large randomization clinical trial. As a result of the underlying disease as
well as the chemotherapy, serious adverse events are very frequently observed
in this patient population (e.g. bleeding, life threatening infections, death
due to progression of the underlying disease). The study will comprise of 4
study visits and as most patients will be hospitalized at the start of therapy
few of these will be additional hospital visits on top of the standard of care.
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
1. 18 years or older
2. Have started or will start voriconazole or isavuconazole (or posaconazole if
voriconazole or isavuconazole cannot be given as per treating physician*s
decision) as antifungal therapy on the baseline visit.
3. For all patients: presence of one of the EORTC/MSG host factors or being
admitted to the ICU with influenza
4 For non-ICU patients or ICU patients without influenza: Meet the EORTC/MSG
clinical criterion.
5 For non-ICU patients or ICU patients without influenza: Meet the mycological
criterion or fulfil inclusion criterion 7.
6. For ICU patients with influenza we consider an isolated positive sputum
culture for Aspergillus spp. insufficient as a mycological criterion.
Therefore, in these patients only one of the following mycological criteria are
acceptable; Serum galactomannan >=0.5, BAL galactomannan >=1.0 or Aspergillus
spp. cultured in BAL fluid.
Exclusion criteria
1. Known history of allergy, hypersensitivity or serious reaction to triazole
or echinocandin antifungals;
2.Patients with chronic invasive aspergillosis or a chronic non-invasive
aspergillus infection (e.g. aspergilloma) defined as the clinical or
radiological sign of infection being present for >28 days.
3. Receipt of itraconazole, voriconazole, posaconazole as prophylaxis for at
least 7 days in the 14 days preceding the date of the first radiological signs
of the Aspergillus infection. Patients in which the most recent serum level of
the triazole given as prophylaxis was subtherapeutic can be included.
4. Receipt of echinocandin prophylaxis for >96 hours in the preceding 7 days
5 Receipt of systemic antifungal treatment with an echinocandin, a
triazole (except fluconazole) or amphotericin B for the current episode of
invasive aspergillosis for a duration of > 96 hours.
6.. For patients in the Netherlands only: Diagnostic testing to exclude
triazole resistance will not be possible (sputum cultures are negative and BAL
sampling will not be performed)
7. ICU patients only: Patients with a sequential organ failure assessment
(SOFA) score >11 at the time of screening for the study are excluded. If
randomization is done >24 hours after screening the calculation should be
repeated before the patient can be randomized (appendix 3)
8. ICU patients only: Patients in which weaning from the ventilator or ECMO
system is deemed unlikely due to irreversible lung damage
9. Patients with any condition which, in the opinion of the investigator, could
affect patient safety, preclude evaluation of response (e.g. because survival
beyond 6 weeks is unlikely due to the underlying disease status)
10. Patient previously included in this study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000627-40-NL |
| ClinicalTrials.gov | NCT04876716 |
| CCMO | NL72950.078.20 |