SepsisNCT04665089
Erythromycin in Septic Patients: Immunomodulatory Role and Clinical Impact
A study testing Erythromycin in people with Sepsis and Septic Shock, run by Tunis University at 1 site in Tunisia.
Trial summary
In sepsis and septic shock, the host response is characterized by a complex of immune-inflammatory reactions; triggered and activated by microbial components. These reactions are controlled by a balance of pro-inflammatory cytokines and anti-inflammatory cytokines. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Septic Shock, Immunoinflammatory Response
- What is being tested?
- Erythromycin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 110 participants
- Where
- 1 siteTunisia
- Study dates
- 1 Jan 2022to 30 Apr 2023
- 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
- a patient in whom the diagnosis of sepsis or septic shock is diagnosed (According to the definitions updated by the sepsis 3 consensus in 2016)
Who cannot join
- Macrolide use for another indication.
- Known allergy to macrolides.
- A corrected QT prolonged (> 440 ms for man and 460 ms for woman) or taking drugs with an increased risk of QT prolongation.
- QT prolongation attributed to erythromycin
- Underlying dysimmunity (unbalanced diabetes, autoimmune disease, etc.)
- Pregnant or breastfeeding woman.
- Death or discharge while participating in the protocol (day 0 to day 6)
- Non-compliance with the protocol
Trial locations and contacts
1 site in 1 country.
Tunisia1 site
intensive care unit of the University Hospital Center La Rabta
Tunis, 1007
About this study
Official title: Immunomodulatory Role and Clinical Impact of Erythromycin in Critically Septic Patients: a Randomized Clinical Trial
In sepsis and septic shock, the host response is characterized by a complex of immune-inflammatory reactions; triggered and activated by microbial components. These reactions are controlled by a balance of pro-inflammatory cytokines and anti-inflammatory cytokines. The imbalance of this immune response is a source of organ dysfunction; major prognostic factor during septic condition. This pretext has created the need for therapies aimed to modulate the overstated of host response. During the past 2 decades, macrolide molecules proved interest to be immunomodulatory agents; due beyond their antibacterial activity. Their regulatory role in the production of cytokines was demonstrated in the management of severe acute community pneumonia.
The investigators hypothesize that the adjunction of macrolides to standard therapy in patients with sepsis or septic shock is associated to a favorable immunomodulatory and clinical effects.
Read the detailed description
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It is considered as the main cause of death in critically ill patients ranging from 20 to 50%. These alarming death rates have prompted several intense research efforts to better understand the mechanisms underlying the pathogenesis of sepsis. Currently, sepsis is recognized as a complex entity created by an immuno-inflammatory reaction of the infected host; triggered and activated by microbial components. This reaction brings together the cellular and humoral immunity defense systems. Activation of the cellular system involves macrophages, polymorphonuclear cells, lymphocytes and endothelial cells.
Therefore, pro-inflammatory cytokines are secreted in order to control the infection (IL-1, IL-6, IL-8, and TNF-alpha). Simultaneously, anti-inflammatory cytokines (IL-4, IL-10) are also released, allowing a local and systemic regulation of the inflammatory cascade. The imbalance of this immune response is a source of organ dysfunction aggravated by the lack of tissue oxygenation.
Understanding that sepsis results from a disproportionate immune-inflammatory response have created the need for therapies aimed to modulate the overstated host response. The agents tested were: anti-endotoxin antibodies, tumor necrosis factor (TNF), anti-TNF-alpha, recombinant human activated protein C (rhAPC), stress-dose hydrocortisone and statins. Most of these clinical trials showed no obvious clinical impact or a limited clinical efficacy.
During the past 2 decades, macrolides molecules were revealed to be immune-modulator agents; beyond their antibacterial activity. Their immune-modulator properties result from their ability to induce the activity of various immune cells and their regulatory role in the production of cytokines. Several cellular targets and mechanisms have been described to explain the immune-modulator effects of macrolides: Respiratory epithelial cells and innate immunity cells. Overall, macrolides decrease the production of pro-inflammatory cytokines by innate and adaptive immunity cells.
In this clinical trial, the investigators are focusing on the effects of macrolides on the pro-inflammatory / anti-inflammatory balance by assaying cytokines and other immune-inflammatory markers during sepsis and septic shock. The main hypothesis is that the use of macrolides in addition to standard therapy in critically septic patients has a favorable immune-modulator and clinical effects compared to critically septic patients not receiving macrolide.
- Conditions
- Sepsis, Septic Shock, Immunoinflammatory Response
- Being tested
- Erythromycin
- Keywords
- sepsis, erythromycin, immunity, inflammation, mortality
- Medical subject headings
- Sepsis, Shock, Septic, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ErythromycinDrug
Also called specific dosages
Before each intervention (either at inclusion: day 0) and after the end of 5 days of erythromycin or placebo (day 6), the following dosages will be performed:
- Pro-inflammatory cytokine (TNF alpha)
- Anti-inflammatory cytokine (IL-10)
- Procalcitonin (PCT) Then, analysis of the variations in the TNF/ IL-10 ratio, the blood count, CRP and PCT parameters (between Day 0 and Day 6)
| Study group | Role | What they receive |
|---|---|---|
| Erythromycin arm | Active comparator | The erythromycin arm (n=55) receives, in addition to the standard antimicrobial therapy, erythromycin 1 g three times per day intravenously: each gram is diluted in 250 ml of 5% glucose serum to be administered over 1 hour for 5 days. Receives: Drug: Erythromycin |
| Placebo arm | Placebo comparator | The placebo arm (n=55) receives, in addition to the standard antimicrobial therapy, isotonic saline, intravenously, 20 ml diluted in 250 ml of 5% glucose serum to be administered over 1 hour for 5 days. Receives: Drug: Erythromycin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change of TNF α / IL-10 ratio
The pro-inflammatory / anti-inflammatory balance will be estimated by measuring the TNF α / IL-10 ratio at baseline and that at day 6. The difference (Δ) of TNF α / IL-10 ratio between day 0 (or baseline) and day 6 will be calculated in each arm then compared between the 2 arms.
Measured: Change from Baseline TNF α / IL-10 ratio at 6 days
Secondary outcomes (4)
mortality
28-day mortality
Measured: 28 days
Procalcitonine
bilogical parameter with measurement of the difference (Δ) in procalcitonine between day 6 and day 0
Measured: At day 0 and day 6 of inclusion
vasopressors requirement in mg/H
maximum dose of vasopressors use
Measured: during follow-up, an average of 28 days
vasopressors requirement in days
time needed of vasopressors use
Measured: during follow-up, an average of 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Dec 2020
- Study start1 Jan 2022
- Primary completion30 Jan 2023
- Study completion30 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)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
- single-blind randomized clinical trial comparing 2 arms: erythromycin versus a placebo
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 110 participants (actual)
Sponsor and investigators
- Lead sponsor
- Tunis University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ahlem Trifi, University Tunis El Manar
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04665089
- Sponsor's protocol ID
- Rabta
- Status last verified
- May 2023
- First submitted
- 20 Nov 2020
- Last updated
- 12 May 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Trifi A, Tlili B, Kallel Sellami M, Feki M, Mehdi A, Seghir E, Messaoud L, Abdellatif S, Ben Lakhal S. Immunologic effect and clinical impact of erythromycin in septic patients: A randomized clinical trial. J Crit Care. 2024 Jun;81:154533. doi: 10.1016/j.jcrc.2024.154533. Epub 2024 Feb 14.
PubMed 38359518
Study at a glance
From the registry record, last updated by the sponsor on 12 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Immunomodulatory Role and Clinical Impact of Erythromycin in Critically Septic Patients: a Randomized Clinical Trial
- ClinicalTrials.gov ID
- NCT04665089
- Acronym / sponsor ID
- Rabta
- Conditions
- Sepsis, Septic Shock, Immunoinflammatory Response
- Keywords
- sepsis, erythromycin, immunity, inflammation, mortality
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 110 participants (actual)
- Lead sponsor
- Tunis UniversityUniversity, hospital or other
- Study start
- 1 Jan 2022 (actual)
- Primary completion
- 30 Jan 2023 (actual)
- Study completion
- 30 Apr 2023 (actual)
- First posted
- 11 Dec 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.
In sepsis and septic shock, the host response is characterized by a complex of immune-inflammatory reactions; triggered and activated by microbial components. These reactions are controlled by a balance of pro-inflammatory cytokines and anti-inflammatory cytokines. The imbalance of this immune response is a source of organ dysfunction; major prognostic factor during septic condition. This pretext has created the need for therapies aimed to modulate the overstated of host response. During the past 2 decades, macrolide molecules proved interest to be immunomodulatory agents; due beyond their antibacterial activity. Their regulatory role in the production of cytokines was demonstrated in the management of severe acute community pneumonia.
The investigators hypothesize that the adjunction of macrolides to standard therapy in patients with sepsis or septic shock is associated to a favorable immunomodulatory and clinical effects.
Detailed description
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It is considered as the main cause of death in critically ill patients ranging from 20 to 50%. These alarming death rates have prompted several intense research efforts to better understand the mechanisms underlying the pathogenesis of sepsis. Currently, sepsis is recognized as a complex entity created by an immuno-inflammatory reaction of the infected host; triggered and activated by microbial components. This reaction brings together the cellular and humoral immunity defense systems. Activation of the cellular system involves macrophages, polymorphonuclear cells, lymphocytes and endothelial cells.
Therefore, pro-inflammatory cytokines are secreted in order to control the infection (IL-1, IL-6, IL-8, and TNF-alpha). Simultaneously, anti-inflammatory cytokines (IL-4, IL-10) are also released, allowing a local and systemic regulation of the inflammatory cascade. The imbalance of this immune response is a source of organ dysfunction aggravated by the lack of tissue oxygenation.
Understanding that sepsis results from a disproportionate immune-inflammatory response have created the need for therapies aimed to modulate the overstated host response. The agents tested were: anti-endotoxin antibodies, tumor necrosis factor (TNF), anti-TNF-alpha, recombinant human activated protein C (rhAPC), stress-dose hydrocortisone and statins. Most of these clinical trials showed no obvious clinical impact or a limited clinical efficacy.
During the past 2 decades, macrolides molecules were revealed to be immune-modulator agents; beyond their antibacterial activity. Their immune-modulator properties result from their ability to induce the activity of various immune cells and their regulatory role in the production of cytokines. Several cellular targets and mechanisms have been described to explain the immune-modulator effects of macrolides: Respiratory epithelial cells and innate immunity cells. Overall, macrolides decrease the production of pro-inflammatory cytokines by innate and adaptive immunity cells.
In this clinical trial, the investigators are focusing on the effects of macrolides on the pro-inflammatory / anti-inflammatory balance by assaying cytokines and other immune-inflammatory markers during sepsis and septic shock. The main hypothesis is that the use of macrolides in addition to standard therapy in critically septic patients has a favorable immune-modulator and clinical effects compared to critically septic patients not receiving macrolide.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- single-blind randomized clinical trial comparing 2 arms: erythromycin versus a placebo
| Arm | Type | Receives |
|---|---|---|
| Erythromycin arm | Active comparator | Drug: ErythromycinThe erythromycin arm (n=55) receives, in addition to the standard antimicrobial therapy, erythromycin 1 g three times per day intravenously: each gram is diluted in 250 ml of 5% glucose serum to be administered over 1 hour for 5 days. |
| Placebo arm | Placebo comparator | Drug: ErythromycinThe placebo arm (n=55) receives, in addition to the standard antimicrobial therapy, isotonic saline, intravenously, 20 ml diluted in 250 ml of 5% glucose serum to be administered over 1 hour for 5 days. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- a patient in whom the diagnosis of sepsis or septic shock is diagnosed (According to the definitions updated by the sepsis 3 consensus in 2016)
Key exclusion criteria (8 listed)
- Macrolide use for another indication.
- Known allergy to macrolides.
- A corrected QT prolonged (> 440 ms for man and 460 ms for woman) or taking drugs with an increased risk of QT prolongation.
- QT prolongation attributed to erythromycin
- Underlying dysimmunity (unbalanced diabetes, autoimmune disease, etc.)
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 |
|---|---|---|
| ErythromycinAlso: specific dosagesBefore each intervention (either at inclusion: day 0) and after the end of 5 days of erythromycin or placebo (day 6), the following dosages will be performed: * Pro-inflammatory cytokine (TNF alpha) * Anti-inflammatory cytokine (IL-10) * Procalcitonin (PCT) Then, analysis of the variations in the TNF/ IL-10 ratio, the blood count, CRP and PCT parameters (between Day 0 and Day 6) | Drug | Erythromycin arm, Placebo arm |
Primary outcome
Change of TNF α / IL-10 ratio
Time frame: Change from Baseline TNF α / IL-10 ratio at 6 days
The pro-inflammatory / anti-inflammatory balance will be estimated by measuring the TNF α / IL-10 ratio at baseline and that at day 6. The difference (Δ) of TNF α / IL-10 ratio between day 0 (or baseline) and day 6 will be calculated in each arm then compared between the 2 arms.
4 secondary outcomes
mortality
Time frame: 28 days
Procalcitonine
Time frame: At day 0 and day 6 of inclusion
vasopressors requirement in mg/H
Time frame: during follow-up, an average of 28 days
vasopressors requirement in days
Time frame: during follow-up, an average of 28 days
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 12 May 2023.
- Derived from this study: PubMed 38359518Trifi A, Tlili B, Kallel Sellami M, Feki M, Mehdi A, Seghir E, Messaoud L, Abdellatif S, Ben Lakhal S. Immunologic effect and clinical impact of erythromycin in septic patients: A randomized clinical trial. J Crit Care. 2024 Jun;81:154533. doi: 10.1016/j.jcrc.2024.154533. Epub 2024 Feb 14.
- Individual participant dataSharing planned: No
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Erythromycin in people with Sepsis and Septic Shock, run by Tunis University at 1 site in Tunisia.
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 1 inclusion and 8 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 12 May 2023. 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 Tunisia. 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.
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?
Change of TNF α / IL-10 ratio (time frame: Change from Baseline TNF α / IL-10 ratio at 6 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 NCT04665089, which also lists 1 linked publication.
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 12 May 2023.