A Phase 3 interventional study of Clarithromycin and Water for injection in Sepsis, Pneumonia and Gram-Negative Bacteria Infection, sponsored by Hellenic Institute for the Study of Sepsis. Completed at 12 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-12-22.
Sponsored by Hellenic Institute for the Study of Sepsis · Phase 3, Interventional, and Treatment
Among 16 studies in Sepsis by Hellenic Institute for the Study of Sepsis — 4 open to participants now, 6 under way, 4 of them phase 3. Sepsis · Hellenic Institute for the Study of Sepsis.
Among the 16 studies in Sepsis by Hellenic Institute for the Study of Sepsis, this one is the 10th largest by enrollment of the 13 interventional ones, is one of 4 that started in 2017, is one of 6 in phase 3, and was the 4th registered.
2,416 studies on the registry are indexed under Sepsis; 541 are open to participants now.
This study's enrollment of 110 is close to the median of 102 across 1,165 interventional studies indexed under Sepsis.
Browse Sepsis studies →4 of the 16 studies in Sepsis by Hellenic Institute for the Study of Sepsis are open now, in 1 country. Each count lists the studies.
Of the 318 Sepsis studies recruiting now, 213 (67%) set no upper age limit and 53 (17%) stop at 75 or younger; 68 take children under 18; 42 take healthy volunteers.
This study: 18 Years and older · all sexes · no healthy volunteers.
The full table on the hub →16 studies; the count open now beside each. This study's row is marked.
First in 2017; this study’s year is marked. 4 started in 2017.
Median enrollment 252 across the 13 interventional studies, 200 across the 3 observational. Of the 9 that completed or were terminated, 0 (0%) have results posted.
Hellenic Institute for the Study of Sepsis is the lead sponsor of 32 studies on the registry; 7 are open to participants now.
2 of the studies in Sepsis by Hellenic Institute for the Study of Sepsis that are under way reach primary completion within a year, 0 of them phase 3. Phase 3 first, then by date:
| Study | Primary completion |
|---|---|
| NCT06694701Hellenic Institute for the Study of SepsisEmapalumab Treatment For Anticipated Clinical Benefit In Sepsis Driven By The Interferon-Gamma Endotype (The EMBRACE Trial) | 2026-11 |
| NCT07927621Hellenic Institute for the Study of SepsisViscoelastic Coagulation Monitoring for Early Identification of Sepsis: The VISION II Study | 2027-05 |
Among the 16 studies in Sepsis by Hellenic Institute for the Study of Sepsis, from their registry updates:
High mortality associated with sepsis and Multiple Organ Dysfunction Syndrome (MODS) calls for alternative, individualized therapies in selected patients that might benefit form specific interventions. Role of macrolides as potential immunomodulatory treatment in sepsis is promising, but unclear. Subgroup analysis of previous large-scale clinical trials on patients with ventilator-associated pneumonia or gram-negative sepsis, showed that addition of clarithromycin to standard antibiotic therapy conferred a significant survival benefit in the subgroup of patients with respiratory dysfunction and MODS. The INCLASS study is aiming to assess the efficacy of intravenous treatment of clarithromycin in the reduction of 28-day mortality among patients suffering from these entities.
Sepsis is a condition with actually rising incidence, estimated around 19 cases per 1000 hospitalizations per year in academic hospitals in USA and similar trends in Europe. It is associated with unacceptably high early (in-hospital) mortality of 40- 50%. Current guidelines promote best practice by early recognition and management with timely antibiotic administration, fluids, vasopressors and early identification/ control of infection source. However, in spite of adherence to more intensive and costly protocols of early goal-directed therapy, no further decrease in mortality is achieved. Syndromic approaches on sepsis and therapies targeting immune modulation are under evaluation and failures may partly be due to incomplete understanding of underlying pathophysiological mechanisms and immunological phases (pro and anti-inflammatory) of sepsis.
Macrolides, such as clarithromycin or azithromycin have been shown beneficial in reducing Chronic Obstructive Pulmonary Disease exacerbations (OR 0.55; 95% Confidence Intervals [CI] 0.39-0.77; p\<0.001) partly through anti-inflammatory properties. Besides, when added to a beta-lactam regimen in community-acquired pneumonia, macrolide therapy was associated with reduced mortality risk (OR 0.67; 95% CI 0.61-0.73; p\<0.001) in a recent meta- analysis of observational studies including 42942 patients. An immunomodulatory effect of macrolides, beyond their antimicrobial action may explain these findings.
Clarithromycin as adjunctive treatment to standard antibiotic therapy has been used by our group in two previous large-scale multi-center Randomised Controlled Trials (RCTs) conducted in Greece after approval from the Greek regulatory authorities. The first RCT studied 200 patients with sepsis due to Ventilator Associated Pneumonia (VAP) ( www.clinicaltrials.gov NCT00297674). Identified pathogens mainly included gram- negative bacteria i.e. Acinetobacter baumannii and Pseudomonas aeruginosa that do not belong to the usual antimicrobial spectrum of macrolides. Although 28-day mortality in both arms was similar, patients assigned to the clarithromycin arm experienced earlier weaning from mechanical ventilation and more rapid resolution of VAP, compared to the placebo arm. In the subgroup of patients with septic shock and multiple organ dysfunction syndrome (MODS), probability of sepsis-related death was significantly lower (OR 3.78 vs 19; p = 0.043). Serious adverse events (SAEs) occurred in 3 (3%) clarithromycin-treated patients, with no clear causative link with the study drug in 2 out of 3 cases. Furthermore, hospitalization costs associated clarithromycin use were significantly reduced (by 7000 euros/ patient) compared to the placebo arm.
The second multi-center RCT compared the efficacy of clarithromycin versus placebo added to standard antibiotic therapy in patients with gram-negative sepsis caused by acute pyelonephritis, intra-abdominal infections and primary gram- negative bacteremia; 600 patients were included (www.clinicaltrials.gov NCT01223690). Overall mortality at 28 days in both arms did not differ, but probability of death due to septic shock and MODS was shown once more lower in the clarithromycin-treated group (OR 3.58 vs 6.21; p = 0.036). Interestingly, survival benefit from clarithromycin was even greater in those patients suffering from adult respiratory distress syndrome (ARDS). SAEs were described in 2 (0.7%) patients treated with clarithromycin, while its use was associated with saving of a median of 1000 euros/ hospitalized patient.
Immunomodulatory effects of clarithromycin in sepsis are not yet elucidated. The analysis of circulating monocytes and of circulating cytokines of patients participating in the first RCT showed that treatment with clarithromycin was associated with a decline in Interleukin-10 (IL-10)/ Tumor Necrosis Factor-α (TNF-α) ratio, greater apoptosis of monocytes, enhanced antigen presentation capacity of monocytes, as well as improved capacity of monocytes for cytokine production suggesting an effect consistent with reversal of sepsis-induced immunosuppression. These findings in conjunction with evidence generated from in vitro and animal experiments suggest modulation of the immune response as the mechanism of action of clarithromycin.
In both RCTs, clarithromycin was administered intravenously at a dose of 1g as continuous one-hour intravenous infusion for three or four days. The drug was safe, well tolerated and cost-effective. However, benefit from treatment in both RCTs was shown only after sub-group analysis of the sub-group of patients with respiratory dysfunction and not when analysis comprised the entire study population. As a consequence, in order to consolidate the benefit of clarithromycin among patients with sepsis and respiratory dysfunction, the INCLASS study is a RCT designed to target a patient population with sepsis and respiratory dysfunction. It also targets a population with infections likely to be caused by Gram-negative bacteria that do not belong to the antimicrobial spectrum of clarithromycin. The study's aims are to assess the effect on mortality associated with the use of clarithromycin as adjunctive treatment in the above setting, as well as to provide insight on different biomarkers modification during treatment, to propose a mechanism of action of this treatment and to perform a cost analysis.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
After enrollment, the placebo arm will receive water for injection at a volume of 20ml diluted to a final volume of 250 ml dextrose in water 5%, infused once daily through intravenous route, within 1 hour, for a duration of four consecutive days.
Drug: Water for injection
After enrollment, the active drug arm will receive 1g of clarithromycin (500 mg powder for concentrate for solution for infusion per vial), dissolved into 20 ml water for injection and then diluted to a final volume of 250 ml dextrose in water 5%. This will be infused through intravenous route, once daily within 1 hour, for a duration of four consecutive days.
Drug: Clarithromycin
Clarithromycin two vials of lyophilised powder for reconstitution as solution for IV administration per patient, once daily, for four consecutive days.
Also known as: Klaricid, Biclar
Water for injection 20 ml will be administered, diluted in D/W 5%, IV, once daily for four consecutive days
Also known as: Sterile Water For Injection
Mortality rate at 28 days
Differences in early (28-day) all-cause mortality rate between clarithromycin and placebo-treated arms
Time frame: 28 days
Mortality rate at 90 days
Differences in middle term (90-day) all-cause mortality rate between clarithromycin and placebo-treated arms
Time frame: 90 days
Mortality rate at 28 days for patients with septic shock
Differences in early (28-day) all-cause mortality rate between clarithromycin and placebo-treated arms in the subgroup of patients with septic shock
Time frame: 28 days
Rate of early sepsis response at 3 days
The number of patients who present at least 25% decrease of day 1 SOFA score on day 3 will be compared between clarithromycin and placebo-treated groups
Time frame: 3 days
Rate of sepsis resolution at 7 days
The number of patients who present at least 25% decrease of day 1 SOFA score on day 7 will be compared between clarithromycin and placebo-treated groups
Time frame: 7 days
New sepsis episode until 28 days
The number of patients who present a new increase of SOFA score by at least 2 points, consequent to infection, after having previously experienced sepsis resolution, will be compared between clarithromycin and placebo-treated groups
Time frame: 28 days
Time to new sepsis episode until 28 days
The time to new sepsis episode, defined as a new increase of SOFA score by at least 2 points, consequent to infection, in patients who have previously experienced sepsis resolution, will be compared between clarithromycin and placebo-treated groups
Time frame: 28 days
Cell population analysis
Flow cytometry will be compared between clarithromycin and placebo-treated arms
Time frame: 10 days
Transcriptome analysis
Expression of messenger Ribonucleic Acid (mRNA) will be compared between clarithromycin and placebo-treated arms
Time frame: 10 days
Metabolome analysis
Metabolites will be compared between clarithromycin and placebo-treated arms
Time frame: 10 days
Microbiome analysis
Gut microbiome composition will be compared between clarithromycin and placebo-treated arms
Time frame: 10 days
Cost of hospitalization
Real cost of hospitalization, i.e. medication administered and interventions performed, in euros (€), will be compared between clarithromycin and placebo-treated groups
Time frame: 28 days
Plan to share: No
This study is completed, as verified in Dec 2020. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Clarithromycin
Hellenic Institute for the Study of Sepsis