SepsisPhase 3NCT01649921
The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis
A Phase 3 study testing Interferon-gamma, Recombinant and Saline 0.9% in people with Sepsis and Septic Shock, run by Radboud University Medical Center at 1 site in Netherlands.
Trial summary
The primary aim of this study is to assess the effects of adjunctive therapy with Interferon (IFN)-gamma on immune function in patients with septic shock in a placebo-controlled manner. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Septic Shock
- What is being tested?
- Interferon-gamma, Recombinant and Saline 0.9%
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 4 participants
- Where
- 1 siteNetherlands
- Study dates
- Nov 2012to Dec 2016
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Written informed consent from patient of legal representative
- Age >18 years
- Presence of septic shock of bacterial origin with evidence of bacterial infection (last 96 hours, with 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), Two SIRS criteria (last 24 hours, fever (>38.3 ˚C), hypothermia (<35.6 ˚C), tachycardia (>90bpm), tachypnea (>20/min), or partial pressure of arterial carbon dioxide (PaCO2) <32 mmHg, or mechanical ventilation, leukocytosis (>12,000/μl), leucopenia (<4,0000/μl), or >10% immature forms), and presence of shock with need for vasopressor therapy to maintain systolic blood pressure (SBP) ≥ 90 mmHg.
Who cannot join
- Pregnancy or lactating
- Subjects with a history of allergy or intolerance to IFN-gamma
- Systemic autoimmune disease, hematologic disease (neoplasma, acute leukemia), transplant patients, or patients on steroid medication receiving a prednisolone equivalent of > 5 mg per day
- Human immunodeficiency virus positivity
- Presence of an advanced directive to withhold or to withdraw life sustaining treatment
- Underlying disease with a prognosis for survival < 3 months, or moribund patient highly likely to die within 24 hours.
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- Cardiopulmonary resuscitation (<72 hours) before enrollment
- Acute myocardial infarction or pulmonary embolization (<72 hours)
- Participation in a clinical trial until 30 days prior to inclusion
- Subjects with a history of documented epileptic seizures
- Subjects with severe renal impairment (creatinine clearance less than 30 mL/min)
- Subjects with severe liver failure (impaired synthesis of proteins such as coagulation factors manifested by increased prothrombin time)
- Subjects with an absolute neutrophil count of less than 500/mm3 at study entry
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis, a Randomised Double-blind Placebo-controlled Pilot (Phase IIIb) Study
The primary aim of this study is to assess the effects of adjunctive therapy with Interferon (IFN)-gamma on immune function in patients with septic shock in a placebo-controlled manner. Moreover, the investigators 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. With use of the results the investigators will obtain in this pilot study, the investigators will conduct a large multicentre clinical trial with IFN-γ.
Read the detailed description
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 (IFN)-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 with no relevant side-effects.
The primary aim of this study is to assess the effects of adjunctive therapy with IFN-gamma on immune function in patients with septic shock in a placebo-controlled manner. Moreover, the investigators 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.
- Conditions
- Sepsis, Septic Shock
- Being tested
- Interferon-gamma, Recombinant, Saline 0.9%
- Keywords
- Sepsis, SIRS, Septic shock, Immunoparalysis, Interferon-gamma
- Medical subject headings
- Sepsis, Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Interferon-gamma, RecombinantDrug
Interferon-gamma (Immukine, Boehringer-Ingelheim, Alkmaar, the Netherlands), 100mcg subcutaneously, on days 0-2-4-7-9-11. 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
Saline 0.9%Other
subcutaneous administration on days 0, 2, 4, 7, 9, and 11.
| Study group | Role | What they receive |
|---|---|---|
| Interferon-gamma | Active comparator | Not described Receives: Drug: Interferon-gamma, Recombinant |
| Saline 0.9% | Placebo comparator | Not described Receives: Other: Saline 0.9% |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary endpoint is the tumor necrosis factor (TNF)-α secretion by ex vivo lipopolysaccharide (LPS)-stimulated leukocytes as a marker of immunosufficiency/antimicrobial response.
Measured: at admission and at days 0, 2, 7, 14 and 28
Secondary outcomes (11)
Outcome of bacterial infection (occurrence of secondary and/or opportunistic infections, duration of antibacterial treatment, microbiological evaluation)
Measured: At days 0, 2, 7, 14 and 28
Hemodynamic stability (noradrenalin infusion rate, amount of infused fluids per day, amount of urine produced per day, daily fluid balance)
Measured: At days 0, 2, 7, 14 and 28
Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes)
Measured: At days 14 and 28
Length of stay at ICU and duration of hospitalization
Measured: At days 28 and 56
Organ function
- Cardiovascular function: lactate level, vasopressor usage, and cardiovascular Sequential Organ Failure Assessment (SOFA) score
- Respiratory function: oxygenation index, Pulmonary Arterial Oxygen Tension (PaO2) / fraction of inspired oxygen (FiO2) (P/F) ratio, and respiratory SOFA score
- Renal function: creatinine level, urine output, renal replacement therapy usage, and renal SOFA score
- Hematologic function: hematologic SOFA score
- Hepatic function: Hepatic SOFA score
Measured: at days 0, 14, and 28
Production of other cytokines by leukocytes ex vivo stimulated with various stimuli (including LPS, peptidoglycan, candida)
Measured: At admission, at days 0, 2, 7, 14, and 28
Markers of "immune status" (including human leukocyte antigen expression on monocytes (mHLA)-DR and programmed death (PD)-1 expression, interleukin (IL)-6 plasma concentration)
Measured: At admission and at days 0, 2, 7, 14, and 28
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).
Measured: At days 0, 14, and 28
Transcriptional activity of leukocytes, including microarrays with a focus on inflammatory pathways
Measured: At admission and at days 0, 2, 7, 14, and 28
Changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence (epigenetic modifications)
Measured: At admission and at days 0, 7, and 28
reversibility of monocytes tolerance
the reversibility of monocytes tolerance by the mean of innate immune training (cytokines production such as TNF and Interleukin (IL)-6 will be assessed).
Measured: Day 0
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jul 2012 (estimated)
- Study startNov 2012
- Primary completionDec 2016
- Study completionDec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Peter Pickkers, MD, PhD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01649921
- Sponsor's protocol ID
- IFN_sepsis
- Status last verified
- Apr 2014
- First submitted
- 23 Jul 2012
- Last updated
- 29 Sep 2017
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 29 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis, a Randomised Double-blind Placebo-controlled Pilot (Phase IIIb) Study
- ClinicalTrials.gov ID
- NCT01649921
- Acronym / sponsor ID
- IFN_sepsis
- Conditions
- Sepsis, Septic Shock
- Keywords
- Sepsis, SIRS, Septic shock, Immunoparalysis, Interferon-gamma
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Nov 2012 (actual)
- Primary completion
- Dec 2016 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 25 Jul 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary aim of this study is to assess the effects of adjunctive therapy with Interferon (IFN)-gamma on immune function in patients with septic shock in a placebo-controlled manner. Moreover, the investigators 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. With use of the results the investigators will obtain in this pilot study, the investigators will conduct a large multicentre clinical trial with IFN-γ.
Detailed description
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 (IFN)-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 with no relevant side-effects.
The primary aim of this study is to assess the effects of adjunctive therapy with IFN-gamma on immune function in patients with septic shock in a placebo-controlled manner. Moreover, the investigators 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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Interferon-gamma | Active comparator | Drug: Interferon-gamma, Recombinant |
| Saline 0.9% | Placebo comparator | Other: Saline 0.9% |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Written informed consent from patient of legal representative
- Age >18 years
- Presence of septic shock of bacterial origin with evidence of bacterial infection (last 96 hours, with 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), Two SIRS criteria (last 24 hours, fever (>38.3 ˚C), hypothermia (<35.6 ˚C), tachycardia (>90bpm), tachypnea (>20/min), or partial pressure of arterial carbon dioxide (PaCO2) <32 mmHg, or mechanical ventilation, leukocytosis (>12,000/μl), leucopenia (<4,0000/μl), or >10% immature forms), and presence of shock with need for vasopressor therapy to maintain systolic blood pressure (SBP) ≥ 90 mmHg.
Key exclusion criteria (13 listed)
- Pregnancy or lactating
- Subjects with a history of allergy or intolerance to IFN-gamma
- Systemic autoimmune disease, hematologic disease (neoplasma, acute leukemia), transplant patients, or patients on steroid medication receiving a prednisolone equivalent of > 5 mg per day
- Human immunodeficiency virus positivity
- Presence of an advanced directive to withhold or to withdraw life sustaining treatment
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Interferon-gamma, RecombinantInterferon-gamma (Immukine, Boehringer-Ingelheim, Alkmaar, the Netherlands), 100mcg subcutaneously, on days 0-2-4-7-9-11. 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 | Drug | Interferon-gamma |
| Saline 0.9%subcutaneous administration on days 0, 2, 4, 7, 9, and 11. | Other | Saline 0.9% |
Primary outcome
The primary endpoint is the tumor necrosis factor (TNF)-α secretion by ex vivo lipopolysaccharide (LPS)-stimulated leukocytes as a marker of immunosufficiency/antimicrobial response.
Time frame: at admission and at days 0, 2, 7, 14 and 28
11 secondary outcomes
Outcome of bacterial infection (occurrence of secondary and/or opportunistic infections, duration of antibacterial treatment, microbiological evaluation)
Time frame: At days 0, 2, 7, 14 and 28
Hemodynamic stability (noradrenalin infusion rate, amount of infused fluids per day, amount of urine produced per day, daily fluid balance)
Time frame: At days 0, 2, 7, 14 and 28
Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes)
Time frame: At days 14 and 28
Length of stay at ICU and duration of hospitalization
Time frame: At days 28 and 56
Organ function
Time frame: at days 0, 14, and 28
Production of other cytokines by leukocytes ex vivo stimulated with various stimuli (including LPS, peptidoglycan, candida)
Time frame: At admission, at days 0, 2, 7, 14, and 28
Markers of "immune status" (including human leukocyte antigen expression on monocytes (mHLA)-DR and programmed death (PD)-1 expression, interleukin (IL)-6 plasma concentration)
Time frame: At admission and at days 0, 2, 7, 14, and 28
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).
Time frame: At days 0, 14, and 28
Transcriptional activity of leukocytes, including microarrays with a focus on inflammatory pathways
Time frame: At admission and at days 0, 2, 7, 14, and 28
Changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence (epigenetic modifications)
Time frame: At admission and at days 0, 7, and 28
reversibility of monocytes tolerance
Time frame: Day 0
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Sep 2017.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Pickkers, MD, PhD principal investigator
Radboud University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Interferon-gamma, Recombinant and Saline 0.9% in people with Sepsis and Septic Shock, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary endpoint is the tumor necrosis factor (TNF)-α secretion by ex vivo lipopolysaccharide (LPS)-stimulated leukocytes as a marker of immunosufficiency/antimicrobial response. (time frame: at admission and at days 0, 2, 7, 14 and 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Sep 2017.