SepsisCOVERSEPNCT04227652
Control of Fever in Septic Patients
A study testing Ibuprofen administration in people with Sepsis and Severe Sepsis, run by University Hospital Ostrava at 1 site in Czechia.
Trial summary
The benefits of fever treatment in critically ill patients remains unclear. The aim of the prospective, randomized clinical trial was to verify the hypothesis that the administration of ibuprofen in order to decrease the fever in septic patients without limited cardiorespiratory reserve leads to decreasing their… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Severe Sepsis, Septic Shock
- What is being tested?
- Ibuprofen administration
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 140 participants
- Where
- 1 siteCzechia
- Study dates
- 3 Sep 2013to 31 Mar 2019
- Phase
- Interventional
- 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
- age >18 years of age
- body temperature >38.3°C within 2 consecutive hours
- anti-microbial therapy for a known or suspected infection
Who cannot join
- patients admitted after successful cardiopulmonary resuscitation (CPR)
- acute myocardial infarction
- brain injury (traumatic and non-traumatic)
- transfer from another ICU after 72 hours
- pregnancy
- antipyretic medication prior to randomization
Show all 9Show fewer
- non-obtaining the informed consent
- moribund condition
- high risk of hemodynamic or respiratory maladaptation on the metabolic effect of fever
Trial locations and contacts
1 site in 1 country.
Czechia1 site
University Hospital Ostrava
Ostrava, Moravian-Silesian Region, 70852
About this study
The benefits of fever treatment in critically ill patients remains unclear. The aim of the prospective, randomized clinical trial was to verify the hypothesis that the administration of ibuprofen in order to decrease the fever in septic patients without limited cardiorespiratory reserve leads to decreasing their prognosis.
Read the detailed description
Fever is a frequently observed part of the organism's response to infection, and it is a well-known fact that it has positive effects, as it inhibits the growth of microorganisms, and potentiates the activity of anti-microbial agents. On the other hand, fever increases the demand of tissues for oxygen and increases the production of carbon dioxide in tissues. Adapting to these metabolic changes requires an efficient cardiorespiratory apparatus. In other words, in patients with a limited cardiorespiratory reserve (typically patients of higher age or patients with a serious disease of the heart or lungs), the beneficial anti-microbial effect of fever may be masked with cardiorespiratory maladaptation to fever-induced metabolic changes. Indeed, one of the randomized clinical trials investigating the effect of "aggressive" antipyretic strategy used in practice (administration of acetaminophen at the temperature > 38.5 degrees Celsius, and addition of physical cooling should the temperature exceed 39.5 degrees Celsius upon the prognosis of critically ill patients showed that the "aggressive" treatment of fever may result in higher mortality when compared with a "permissive" approach, i.e. an approach when the treatment of fever is initiated only after the body temperature has exceeded 40 degrees Celsius. The study differs remarkably from other studies performed among the population of critically ill patients, and also from studies, which did not manifest the effect of fever treatment upon the mortality of patients, with the age of patients. The average age of patients in both arms of the study was only 47 years of age, whereas the average age of patients in other studies was usually around 60 years of age. It is thus possible to presume that, due to the lower age, the patients in this study possessed a sufficient cardiorespiratory reserve for adaptation to metabolic changes induced with fever, which may have enabled a full manifestation of its anti-microbial effect, and may have led to better patient prognosis. The mortality rate in the group of patients with the "permissive" approach to fever treatment was only 2.6 percent, whereas, in the group of patients with the "aggressive" treatment, the mortality rate was 15.9 percent (p=0.06); due to this fact, the study was prematurely terminated by the Ethics Committee. Based on this study, we decided to test the hypothesis that the administration of ibuprofen in order to decrease the fever would lead to a worsening of the patient prognosis. Ibuprofen was selected due to its potent antipyretic effect, and also due to the fact that the favorable effect of its anti-inflammatory effect upon the prognosis of patients with sepsis has not been fully demonstrated.
- Conditions
- Sepsis, Severe Sepsis, Septic Shock
- Being tested
- Ibuprofen administration
- Keywords
- sepsis, severe sepsis, septic shock, fever, ibuprofen, physiological reserves
- Medical subject headings
- Sepsis, Shock, Septic, Fever
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ibuprofen administrationDrug
Administration of ibuprofen, according to treatment recommendations - per orally, into the nasogastric tube, or in the form of a suppository
| Study group | Role | What they receive |
|---|---|---|
| Aggressive treatment strategy | Experimental | The antipyretic strategy was initiated immediately upon increase of the temperature above 38.3°C. The antipyretic strategy consisted of administration of ibuprofen (per-orally or into the nasogastric tube, or rectal administration in the form of a suppository) in therapeutical dose, alway supplemented with physical cooling in cases when the temperature exceeded 39.5°C. The body temperature was measured in the urinary bladder. Receives: Drug: Ibuprofen administration |
| Conservative treatment strategy | Experimental | The antipyretic strategy was initiated only after the body temperature exceeded 39.5°C. The antipyretic strategy consisted of administration of ibuprofen (per-orally or into the nasogastric tube, or rectal administration in the form of a suppository) in therapeutical dose, alway supplemented with physical cooling in cases when the temperature exceeded 39.5°C. The body temperature was measured in the urinary bladder. Receives: Drug: Ibuprofen administration |
What is being measured
The primary outcome is the main question the study is designed to answer.
SOFA score value
The SOFA score (Sequential Organ Failure Assessment) was measured on Day 3 and Day 7
Measured: up to 7 days
Secondary outcomes (8)
Serum interleukin-6 level
The serum interleukin-6 level was measured on Day 3 and Day 7
Measured: up to 7 days
Serum procalcitonine level
The serum procalcitonine level was measured on Day 3 and Day 7
Measured: up to 7 days
Serum lactate level
The serum lactate level was measured on Day 3 and Day 7
Measured: up to 7 days
Central venous oxygen saturation
The central venous oxygen saturation was measured on Day 3 and Day 7
Measured: up to 7 days
Duration of artificial ventilation
The duration of artificial ventilation in days was observed
Measured: 1 month
Duration of vasopressor support
The duration of vasopressor support in days was observed
Measured: 1 month
Length of ICU stay
The length of ICU stay in days was observed
Measured: 1 month
Length of hospital stay
The length of hospital stay in days was observed
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2020
- Study start3 Sep 2013
- Primary completion28 Feb 2019
- Study completion31 Mar 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- 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 N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The study subjects were enrolled in two parallel groups.
- Masking
- None (open label)
- Enrolment
- 140 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital Ostrava
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Roman Kula, MD,CSc., Principal investigator, University Hospital Ostrava
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04227652
- Sponsor's protocol ID
- FNO-KARIM-13-COVERSEP
- Other IDs
- RVO-FNOs/2013-2
- Acronym
- COVERSEP
- Status last verified
- Jan 2020
- First submitted
- 10 Jan 2020
- Last updated
- 14 Jan 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: There exists no plan to make individual participant data available to other researchers.
Publications
Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005 Winter;6(4):369-75. doi: 10.1089/sur.2005.6.369.
PubMed 16433601Young P, Saxena M, Bellomo R, Freebairn R, Hammond N, van Haren F, Holliday M, Henderson S, Mackle D, McArthur C, McGuinness S, Myburgh J, Weatherall M, Webb S, Beasley R; HEAT Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med. 2015 Dec 3;373(23):2215-24. doi: 10.1056/NEJMoa1508375. Epub 2015 Oct 5.
PubMed 26436473Ye S, Xu D, Zhang C, Li M, Zhang Y. Effect of Antipyretic Therapy on Mortality in Critically Ill Patients with Sepsis Receiving Mechanical Ventilation Treatment. Can Respir J. 2017;2017:3087505. doi: 10.1155/2017/3087505. Epub 2017 Mar 12.
PubMed 28386165Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997 Mar 27;336(13):912-8. doi: 10.1056/NEJM199703273361303.
PubMed 9070471
Study at a glance
From the registry record, last updated by the sponsor on 14 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Control of Fever in Septic Patients
- ClinicalTrials.gov ID
- NCT04227652
- Acronym / sponsor ID
- COVERSEP / FNO-KARIM-13-COVERSEP
- Conditions
- Sepsis, Severe Sepsis, Septic Shock
- Keywords
- sepsis, severe sepsis, septic shock, fever, ibuprofen, physiological reserves
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 140 participants (actual)
- Lead sponsor
- University Hospital OstravaUniversity, hospital or other
- Study start
- 3 Sep 2013 (actual)
- Primary completion
- 28 Feb 2019 (actual)
- Study completion
- 31 Mar 2019 (actual)
- First posted
- 13 Jan 2020 (actual)
- 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 benefits of fever treatment in critically ill patients remains unclear. The aim of the prospective, randomized clinical trial was to verify the hypothesis that the administration of ibuprofen in order to decrease the fever in septic patients without limited cardiorespiratory reserve leads to decreasing their prognosis.
Detailed description
Fever is a frequently observed part of the organism's response to infection, and it is a well-known fact that it has positive effects, as it inhibits the growth of microorganisms, and potentiates the activity of anti-microbial agents. On the other hand, fever increases the demand of tissues for oxygen and increases the production of carbon dioxide in tissues. Adapting to these metabolic changes requires an efficient cardiorespiratory apparatus. In other words, in patients with a limited cardiorespiratory reserve (typically patients of higher age or patients with a serious disease of the heart or lungs), the beneficial anti-microbial effect of fever may be masked with cardiorespiratory maladaptation to fever-induced metabolic changes. Indeed, one of the randomized clinical trials investigating the effect of "aggressive" antipyretic strategy used in practice (administration of acetaminophen at the temperature > 38.5 degrees Celsius, and addition of physical cooling should the temperature exceed 39.5 degrees Celsius upon the prognosis of critically ill patients showed that the "aggressive" treatment of fever may result in higher mortality when compared with a "permissive" approach, i.e. an approach when the treatment of fever is initiated only after the body temperature has exceeded 40 degrees Celsius. The study differs remarkably from other studies performed among the population of critically ill patients, and also from studies, which did not manifest the effect of fever treatment upon the mortality of patients, with the age of patients. The average age of patients in both arms of the study was only 47 years of age, whereas the average age of patients in other studies was usually around 60 years of age. It is thus possible to presume that, due to the lower age, the patients in this study possessed a sufficient cardiorespiratory reserve for adaptation to metabolic changes induced with fever, which may have enabled a full manifestation of its anti-microbial effect, and may have led to better patient prognosis. The mortality rate in the group of patients with the "permissive" approach to fever treatment was only 2.6 percent, whereas, in the group of patients with the "aggressive" treatment, the mortality rate was 15.9 percent (p=0.06); due to this fact, the study was prematurely terminated by the Ethics Committee. Based on this study, we decided to test the hypothesis that the administration of ibuprofen in order to decrease the fever would lead to a worsening of the patient prognosis. Ibuprofen was selected due to its potent antipyretic effect, and also due to the fact that the favorable effect of its anti-inflammatory effect upon the prognosis of patients with sepsis has not been fully demonstrated.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- The study subjects were enrolled in two parallel groups.
| Arm | Type | Receives |
|---|---|---|
| Aggressive treatment strategy | Experimental | Drug: Ibuprofen administrationThe antipyretic strategy was initiated immediately upon increase of the temperature above 38.3°C. The antipyretic strategy consisted of administration of ibuprofen (per-orally or into the nasogastric tube, or rectal administration in the form of a suppository) in therapeutical dose, alway supplemented with physical cooling in cases when the temperature exceeded 39.5°C. The body temperature was measured in the urinary bladder. |
| Conservative treatment strategy | Experimental | Drug: Ibuprofen administrationThe antipyretic strategy was initiated only after the body temperature exceeded 39.5°C. The antipyretic strategy consisted of administration of ibuprofen (per-orally or into the nasogastric tube, or rectal administration in the form of a suppository) in therapeutical dose, alway supplemented with physical cooling in cases when the temperature exceeded 39.5°C. The body temperature was measured in the urinary bladder. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- age >18 years of age
- body temperature >38.3°C within 2 consecutive hours
- anti-microbial therapy for a known or suspected infection
Key exclusion criteria (9 listed)
- patients admitted after successful cardiopulmonary resuscitation (CPR)
- acute myocardial infarction
- brain injury (traumatic and non-traumatic)
- transfer from another ICU after 72 hours
- pregnancy
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 |
|---|---|---|
| Ibuprofen administrationAdministration of ibuprofen, according to treatment recommendations - per orally, into the nasogastric tube, or in the form of a suppository | Drug | Aggressive treatment strategy, Conservative treatment strategy |
Primary outcome
SOFA score value
Time frame: up to 7 days
The SOFA score (Sequential Organ Failure Assessment) was measured on Day 3 and Day 7
8 secondary outcomes
Serum interleukin-6 level
Time frame: up to 7 days
Serum procalcitonine level
Time frame: up to 7 days
Serum lactate level
Time frame: up to 7 days
Central venous oxygen saturation
Time frame: up to 7 days
Duration of artificial ventilation
Time frame: 1 month
Duration of vasopressor support
Time frame: 1 month
Length of ICU stay
Time frame: 1 month
Length of hospital stay
Time frame: 3 months
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 14 Jan 2020.
- Background: PubMed 16433601Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005 Winter;6(4):369-75. doi: 10.1089/sur.2005.6.369.
- Background: PubMed 26436473Young P, Saxena M, Bellomo R, Freebairn R, Hammond N, van Haren F, Holliday M, Henderson S, Mackle D, McArthur C, McGuinness S, Myburgh J, Weatherall M, Webb S, Beasley R; HEAT Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med. 2015 Dec 3;373(23):2215-24. doi: 10.1056/NEJMoa1508375. Epub 2015 Oct 5.
- Background: PubMed 28386165Ye S, Xu D, Zhang C, Li M, Zhang Y. Effect of Antipyretic Therapy on Mortality in Critically Ill Patients with Sepsis Receiving Mechanical Ventilation Treatment. Can Respir J. 2017;2017:3087505. doi: 10.1155/2017/3087505. Epub 2017 Mar 12.
- Background: PubMed 9070471Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997 Mar 27;336(13):912-8. doi: 10.1056/NEJM199703273361303.
- Individual participant dataSharing planned: No. There exists no plan to make individual participant data available to other researchers.
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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.
Roman Kula, MD,CSc. principal investigator
University Hospital Ostrava
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Ibuprofen administration in people with Sepsis and Severe Sepsis, run by University Hospital Ostrava at 1 site in Czechia.
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 9 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 14 Jan 2020. 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 Czechia. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
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?
SOFA score value (time frame: up to 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04227652, which also lists 4 linked publications.
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 14 Jan 2020.