The primary aim of this pilot-study is to assess safety and the effects on immune function in patients with septic shock of adjunctive therapy with IFN-gamma, in a placebo-controlled manner. The data obtained will allow us to do a powercalculation…
ID
Source
Brief title
Condition
- Other condition
- Ancillary infectious topics
Synonym
Health condition
sepsis
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the (preliminary) efficacy of IFN-γ as adjunctive treatment in
combination with standard therapy for the treatment of patients presenting with
septic shock, by assessment of a series of surogate immunological parameters.
The primary endpoint is the TNF-α secretion by ex vivo LPS-stimulated
leukocytes as a marker of immunosuficiency/antimicrobial response.
Secondary outcome
- Outcome of bacterial infection (occurrence of secondary and/or opportunistic
infections, duration of antibacterial treatment, microbiological evaluation)
- Hemodynamic stability (noradrenalin infusion rate, amount of infused fluids
per day, amount of urine produced per day, daily fluid balance)
- Mortality (including time to death) at week 2 and week 6 after end of
treatment (all causes)
- Length of stay at ICU and duration of hospitalization
- Organ function:
* Cardiovascular function: lactate level, vasopressor usage, and
cardiovascular Sequential Organ Failure Assessment (SOFA) score
* Respiratory function: oxygenation index, PaO2/FiO2 (P/F) ratio, and
respiratory SOFA score
* Renal function: creatinin level, urine ouput, renal replacement
therapy usage, and renal SOFA score
* Hematologic function: hematologic SOFA score
* Hepatic function: Hepatic SOFA score
- Production of cytokines by leukocytes ex vivo stimulated with various stimuli
(including LPS, peptidoglycan, candida)
- Markers of *immune status* (including mHLA-DR and PD-1 expression, IL-6
plasma concentration)
- To determine the correlation between the level of immunoparalysis (indicated
by the commonly used marker mHLA-DR and new markers of *immune status* found),
and effectiveness of IFN-γ (indicated by TNF-α secretion by ex vivo
LPS-stimulated PBMC*s).
- Transcriptional activity of leukocytes, including microarrays with a focus on
inflammatory pathways
- Changes in phenotype or gene expression caused by mechanisms other than
changes in the underlying DNA sequence (epigenetic modifications)
Background summary
Sepsis is the leading cause of death in the ICU with an estimated 6 million
victims per year worldwide. Although septic shock is traditionally viewed as an
excessive systemic inflammatory reaction to invasive microbial pathogens,
pharmacological suppression of the innate immune response in sepsis has proved
to be unsuccessful. An important reason for this might be that the vast
majority of septic patients survive the initial pro-inflammatory hit, but die
in the subsequent immunosuppressed state due to secondary/opportunistic
infections. This so-called *immunoparalysis* is increasingly recognized as the
overriding immune dysfunction in septic patients. Reversal of sepsis-induced
immunoparalysis is therefore a promising adjunctive treatment for patients
presenting with septic shock.
It was demonstrated that interferon-gamma can reverse immunoparalysis in vitro
and in vivo in animals and in healthy volunteers. Moreover, in a case-series
of septic patients interferon-gamma treatment leaded to reversal of
immunoparalysis, reduction in mechanical ventilation time and length of stay.
Study objective
The primary aim of this pilot-study is to assess safety and the effects on
immune function in patients with septic shock of adjunctive therapy with
IFN-gamma, in a placebo-controlled manner. The data obtained will allow us to
do a powercalculation for a subsequent larger multi-centre clinical trial.
Moreover, we want to evaluate new markers that could be used to identify
patients with immunoparalysis, and to monitor the patient*s immunological
response to IFN-γ. In addition, mechanistic studies will be performed to
further elucidate mechanisms (such as epigenetic modifications) behind
immunoparalysis and the effects of IFN-γ on these mechanisms.
Study design
A randomised double-blind placebo-controlled pilot (Phase IIIb) study: 20
non-neutropenic patients with documented bacterial septic shock fulfilling the
enrollment criteria (shown in paragraph 5 of the study protocol) will be
randomized to receive either interferon-gamma or placebo in a ratio 1:1.
Interferon gamma will be administered subcutaneous at a dose of 100 µg/day on
days 0-2-4-7-9-11(thrice weekly). Administration of interferon-gamma is to be
discontinued after 12 days in all patients, or earlier if antibacterial drugs
are discontinued earlier. interferon-gamma treatment will be initiated when
the noradrenalin dose is reduced to 50% of maximum dose, ensuring that the
sepsis-induced pro-inflammatory phase has passed. The first day of study drug
administration is denoted as day 1. Once entered, the patient remains in the
study for 28 days (4 weeks). This time, from first study drug administration to
week 4 is defined as the *study period*. All patients will be assessed
according to clinical, microbiological and immunological criteria at regular
intervals during and at the end of the study period. Mortality will be assessed
at 2 and 4 weeks. Blood sampling will be collected at different time points
during the follow-up. They will include 3 x 10 ml blood collected in EDTA tubes
and 2.5 ml blood collected in Paxgene tubes for identification of host response
biomarkers. A baseline assessment will be conducted prior to randomization into
the study and initiation of study drug therapy.
Intervention
Interferon gamma will be administered subcutaneous at a dose of 100 µg/day on
days 1-3-5-8-10-12 (thrice weekly). Administration of IFN-* is to be
discontinued after 12 days in all patients, or earlier if antibacterial drugs
are discontinued earlier. IFN-* treatment will be initiated when the
noradrenalin dose is reduced to 50% of maximum dose, ensuring that the
sepsis-induced pro-inflammatory phase has passed.
Study burden and risks
Blood sampling will be collected at 7 different time points during the
follow-up. They will include 3 x 10 ml blood collected in EDTA tubes and 2.5 ml
blood collected in Paxgene tubes for identification of host response biomarkers.
Adverse reactions to systemic IFN-* include fever, chills, fatigue, myalgias
and headache. These influenza-like symptoms are typically mild, decrease over
time, and can usually be managed with prophylactic antipyretics. Other common
adverse reactions include rash and depression. Reversible neutropenia can
occur. Data from clinical trials, however, indicate that clinically significant
hematologic abnormalities and other serious adverse reactions are infrequent
even when patients are treated for years. Exacerbation of multiple sclerosis
has been described. IFN-γ treatment in septic patients and healthy volunteers
was tolerated well
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. Written informed consent from patient of legal representative
2. Age >18 years
3. Presence of septic shock of bacterial origin (A-C required):
A. Evidence of bacterial infection (last 96 hours), at least one: pathogenic microorganism in blood, sputum, urine, normally sterile body fluid, or on central venous catheter; Focus of infection identified (e.g. ruptured bowel, purulent drainage/sputum); or leukocytes in normally sterile body fluid
B. Two SIRS criteria (last 24 hours): fever (>38.3 *C), hypothermia (<35.6 *C), tachycardia (>90bpm), tachypnea (>20/min), or PaCO2 <32 mmHg, or mechanical ventilation, leukocytosis (>12,000/µl), leucopenia (<4,0000/µl), or >10% immature forms.
C. Presence of shock with need for vasopressor therapy to maintain SBP >= 90 mmHg.
Exclusion criteria
1. Pregnancy or lactating
2. Subjects with a history of allergy or intolerance to IFN-*
3. Systemic autoimmune disease, hematologic disease (neoplasma, acute leukemia), transplant patients, or patients on steroid medication receiving a prednisolon equivalent of > 5 mg per day
4. Human immunodeficiency virus positivity
5. Presence of an advanced directive to withhold or to withdraw life sustaining treatment
6. Underlying disease with a prognosis for survival < 3 months, or moribund patient highly likely to die within 24 hours.
7. Cardiopulmonary resuscitation (<72 hours) before enrolment
8. Acute myocardial infarction or pulmonary embolisation (<72 hours)
9. Participation in a clinical trial until 30 days prior to inclusion
10. Subjects with a history of documented epileptic seizures
11. Subjects with severe renal impairment (creatinine clearance less than 30 mL/min)
12. Subjects with severe liver failure (impaired synthesis of proteins such as coagulation factors manifested by increased prothrombine time)
13. Subjects with an absolute neutrophil count of less than 500/mm3 at study entry
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 |
|---|---|
| Other | ClinicalTrials.gov nr volgt |
| EudraCT | EUCTR2012-002491-14-NL |
| CCMO | NL40914.091.12 |