This study has been transitioned to CTIS with ID 2024-510816-55-00 check the CTIS register for the current data. The primary objective of the study is to evaluate the efficacy and safety and rIFN-γ as adjunctive treatment in combination…
ID
Source
Brief title
Condition
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study endpoint is the time to first negative blood culture.
Secondary outcome
- 1. The time to treatment success (resolution of infection). To achieve this
endpoint of resolution of infection, the following criteria are to be met:
microbiological eradication of Candida from the blood and any other site of
infection; resolution of fever; resolution of other diagnostic variables, such
as imaging results, where applicable; and no new signs of infection. The time
at which all the variables are met is defined as the date of resolution of
infection. Treatment is considered to have failed if new signs of disease have
emerged, when none of the other criteria of resolution have been met, when
antifungal treatment is changed for any reason, or when a patient withdraws
from the study before resolution of infection has been documented. Cases are
scored to have improved if no new signs of disease are present and at least one
of the other criteria of resolution has been met.
- 2. Percentage of patients with Mycological Outcomes at end of study treatment
(EOST), end of treatment (EOT), and 2 and 4 weeks after end of treatment (EOT).
- 3. Percentage of patients with Treatment Success at end of treatment (EOT),
and 14 and 28 days after end of treatment (EOT).
- 4. Overall survival at Study Day 28.
- 5. Number of patients with Treatment Emergent Adverse Events (TEAEs). (Time
frame 49 days)
- 6. Evaluation of patient status at end of rIFN-γ treatment including organ
(dys)function (Sequential Organ Failure Assessment [SOFA] score), and adverse
events. (Time frame 14 days)
- 7. Nutritional status (body weight, BMI), nutritional blood parameters
(prealbumin, total lymphocytes, cholesterol). (Time frame 49 days)
- 8. Genetics and transcriptomics
- 9. Gut microbiota composition and Candida genomics and metabolomics.
- 10. Changes in circulating cytokines, biomarkers, LAP activation,
inflammasome, immunoprofiling.
Background summary
General introduction
Fungal infections are commonly described in the general population. Most of
these infections are superficial and easily treated. However, the incidence of
invasive fungal infections is increasing as a result of the use of invasive
medical interventions, immunosuppressive treatment for autoimmune diseases and
cancer, and the HIV pandemic. These invasive infections are associated with a
high morbidity and mortality in the general population and hospitalized and
intensive care unit patients. Despite development of novel therapeutic
strategies, the burden and death due to fungal infections remains unacceptably
high. Candida is one of the most common causes of these invasive fungal
infections.
Antifungal immunity
Candida is considered an opportunistic pathogen, so an inadequate host defence,
rather than the virulence of the fungus, is associated with the intensity of
Candida infection. It is widely adopted that phagocytic cells play a crucial
role in immunity to fungal infections. This is supported by the high prevalence
of invasive fungal infections in patients with neutropenia or an defect in
phagocyte NADPH oxidase (chronic granulomatous disease). Phagocytes are
activated to kill fungi by pro-inflammatory cytokines as interferon gamma
(IFN-γ) and interleukin 17 (IL-17) produced by Th1 and Th17 lymphocytes. Also
CD4 T-lymphocyte immunodeficiencies are associated with invasive fungal
infections(6). Interventions to stimulate the host defence against fungi have
been proposed consisting of colony-stimulating factors based on the conclusion
that neutrophils play a central role in the host defence against Candida and
recombinant IFN-γ since the Th1 and Th17 responses are essential in antifungal
immunity.
Interferon-gamma
IFN-γ is a cytokine that is critical for innate and adaptive immunity against
infection since it activates monocytes that increases their antigen presenting
capacity by upregulation of co-stimulatory and HLA molecules and primes for
pro-inflammatory cytokine responses. Recombinant IFN-γ (rIFN-γ) as an adjuvant
immunotherapy has been studied the last decades. It has been shown that rIFN-γ
activates macrophages and polymorphonuclear neutrophils against Candida
infection, and reduces fungal burden in mice with disseminated candidiasis(7).
In a trial with patients with chronic granulomatous disease the use of rIFN-γ
was shown successfully protect against aspergillosis(8). Therefore, the IDSA
Guideline state administration of rIFN-γ could be considered as an escape
medicine in patients with severe or refractory invasive fungal infections. The
addition of rIFN-γ to standard treatment in HIV-positive patients with
cryptococcal meningitis was shown to be safe to use and showed faster fungal
clearance. Combining the results with the knowledge on antifungal host defence,
a potential benefit of rIFN-γ immunotherapy can be suggested in patients with
invasive fungal infections as candidemia.
Study objective
This study has been transitioned to CTIS with ID 2024-510816-55-00 check the CTIS register for the current data.
The primary objective of the study is to evaluate the efficacy and safety and
rIFN-γ as adjunctive treatment in combination with standard therapy for the
treatment of patients with candidemia. Efficacy is defined as clearance of
candidemia within the first 7 days of treatment, taking into account mortality.
The secondary objectives of this study are:
• To evaluate new markers that could be used to identify patients that respond
to immunotherapy with rIFN-γ.
• To identify markers that can monitor the patient*s immunological and clinical
response to rIFN-γ immunotherapy.
• To perform mechanistic studies to further elucidate mechanisms that are
important for host defence against candidemia and the effects of rIFN-γ on
these mechanisms.
Study design
This study will be a randomized open label interventional phase 2 pilot study
of the safety and efficacy of rIFN-γ in patients with candidemia. All patients
with candidemia will be randomized between adjunctive rIFN-γ immunotherapy
(100microgram subcutaneous three times a week for two weeks) in combination
with standard therapy or only standard therapy according to ESCMID/EFISG
(Europe) or IDSA (US) guidelines. We will assess the effect on clinical outcome
and investigate relevant biomarkers that can guide this immunotherapeutic
approach.
Intervention
In this study, patients with documented candidemia fulfilling the enrolment
criteria will be randomized in a ratio 1:1 to receive either human rIFN-γ or
standard therapy. rIFN-γ will be administered subcutaneous at a dose of 100 µg/
day on days 0-2-4-7-9-11 (thrice weekly). Administration of rIFN-γ is to be
discontinued after twelve days in all patients
Study burden and risks
Many clinical trials pose only a minimal additional risk to subject safety
compared to normal clinical practice. According to the EU clinical trial
regulation 536/2014(15), these low-intervention clinical trials are of crucial
importance for assessing standard treatments and diagnoses, thereby optimizing
the use of medicinal products and thus contributing to a high level of public
health. Trials like these should be subject to less stringent rules, as regards
monitoring, requirements for the contents of the master file and traceability
of investigational medicinal products. The published scientific evidence
supporting the safety and efficacy of an investigational medicinal product not
used in accordance with the terms of the marketing authorization could include
high quality data published in scientific journal articles, as well as
national, regional or institutional treatment protocols, health technology
assessment reports or other appropriate evidence.
We consider the current study a low intervention clinical trial in line with
the definition from the EU clinical trial regulation 536/2014(15) for the
following reasons:
• rIFN-γ as investigational medicinal product is authorised. Also, the use and
dose are supported by the EMA. Therefore, the additional risk for participation
is reduced to minimum compared to standard treatment.
• rIFN-γ therapy has been used in clinics for a long time in the fields of
rheumatology and oncology and has a well-known safety profile. Moreover, rIFN-γ
is already licensed as a prophylactic agent for patients with chronic
granulomatous disease based on a randomized trial in which the number and
severity of infections was reduced by rIFN-γ therapy(16).
• The IDSA Guideline state that adjunctive treatment with rIFN-γ can be
considered for severe and refractory aspergillosis(9).
• rIFN-γ is proposed to be safe as a treatment for invasive fungal infections
in a high risk population (after allogeneic hematopoietic stem cell
transplantation)(17).
• We already performed a pilot study which provided evidence that immunotherapy
with rIFN-γ is of potential benefit in patients with fungal sepsis(11).
• The additional diagnostic and monitoring procedures besides the treatment
with the investigational product do not pose more than minimal risk and burden.
This is fully in line with EU clinical trial regulation 536/2014 definition of
a low intervention clinical trial.
Given the vulnerable population, we set the risk at moderate according to NFU
guidelines.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
Males or non-pregnant females (who must agree to use barrier methods of
contraception during the study therapy period, women of childbearing age must
have a negative urine pregnancy or serum test at baseline).
Subjects who are 18 years of age or older.
Subjects with at least one positive blood culture isolation of Candida species
from a specimen drawn within 120 hours prior to study entry.
Subjects who have clinical evidence of infection sometime within 120 hours
prior to enrolment, including at least one of the following:
-Temperature >37.8 *C on two occasions at least four hours apart or one
measurement > 38.2 *C
-Systolic blood pressure <90 or a >30 mmHg decrease in systolic blood pressure
from the subject's normal baseline or the need for vassopressive therapy.
-Signs of inflammation (swelling, heat, erythema, purulent drainage) from a
site infected with Candida (e.g. joint, skin, eye, bone, oesophagus).
-Radiologic findings of invasive candidiasis.
Subject or their legal representative must sign a written informed consent form.
- In case a patient eligible to participate in this study is incapacitated and
as such unable to personally provide informed consent, a written consent form
must be signed by their legal representative.
- Only incapacitated patients that can be expected to regain the capability to
consent will be included in this study. In this case, informed consent will be
discussed personally with the study participant after recovery.
- The inclusion of incapacitated subjects will only be performed under the
above conditions in a country in which such an approach is legal and deemed
ethically acceptable.
Exclusion criteria
Subjects with a history of allergy or intolerance to rIFN-γ or any other IMP
ingredient or with a history of immediate type hypersensitivity to latex/rubber.
Subjects with a history of documented epileptic seizures.
Subjects with severe liver failure (>5x upper limit AST or ALT or impaired
synthesis of proteins such as coagulation factors manifested by increased
prothrombin time).
Treatment with heterologous serum proteins, or immunological preparations such
as vaccines, toxins, serums and allergens within three days before trial
enrolment.
Women who are pregnant or lactating.
Subjects who are unlikely to survive more than 24 hours.
Subjects who have failed previous systemic antifungal therapy for the Candida
spp. infection which is being studied.
Subjects who have received more than 120 hours of systemic antifungal therapy
for the current episode, within 120 hours prior to study entry.
With respect to incapacitated subjects:
- Any patient that is deemed incapable of personally providing informed consent
due to a neurodegenerative disease, genetic syndrome, and/or perinatal
asphyxia, will not be eligible for inclusion in this trial.
- Any incapacitated subject that is not expected to recover to a point where
they will personally be able to provide informed consent will not be eligible
for inclusion in this trial.
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 |
|---|---|
| EU-CTR | CTIS2024-510816-55-00 |
| EudraCT | EUCTR2020-003204-13-NL |
| ClinicalTrials.gov | NCT04979052 |
| CCMO | NL74527.091.21 |