Ignite Creation Date:
2024-05-06 @ 3:41 PM
Last Modification Date:
2024-10-26 @ 1:55 PM
Study NCT ID:
NCT04724044
Status:
COMPLETED
Last Update Posted:
2023-12-12
First Post:
2021-01-20
Brief Title:
Anti-inflammatory Action of Oral Clarithromycin in Community-acquired Pneumonia
Sponsor:
Hellenic Institute for the Study of Sepsis
Organization:
Hellenic Institute for the Study of Sepsis
Study Overview
Official Title:
A Randomized Clinical Trial of Oral Clarithromycin in Community-acquired Pneumonia to Attenuate Inflammatory Responses and Improve Outcomes the ACCESS Clinical Trial
Status:
COMPLETED
Status Verified Date:
2023-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ACCESS
Brief Summary:
Traditional management of community-acquired pneumonia CAP relies on the prompt administration of antimicrobials that target the most common causative pathogens Retrospective analysis of observational clinical studies in CAP showed that the addition of macrolides to standard antibiotic therapy conferred a significant survival benefit The proposed benefit of macrolides is coming from their anti-inflammatory mode of action An RCT that proves the attenuation of the high inflammatory burden of the host with CAP after addition of clarithromycin in the treatment regimen is missing This RCT is aiming to prove that addition of oral clarithromycin to a β-lactam rapidly attenuates the high inflammatory burden of the host in CAP
Detailed Description:
Community-acquired pneumonia CAP is one of the most common bacterial infections and a leading cause of death globally since many patients deteriorate into sepsis and organ dysfunction Traditional management relies on the prompt administration of antimicrobials that target the most common causative pathogens namely Streptococcus pneumoniae Mycoplasma pneumoniae Chlamydophila pneumoniae and Legionella pneumophila Although there was some hesitancy in the former guidelines of the Infectious Diseases Society of America IDSA and of the American Thoracic Society ATS to suggest a clear-cut role of macrolides for the management of CAP the new guidelines published by the ATS in 2019 clearly suggest for the management of all cases of CAP either treated as out-patients or as in-patients with a combination of β-lactam with macrolides
The shift in the position of ATS expressed in the 2019 guidelines is coming from the growing body of evidence that the addition of a macrolide in the treatment regimen of CAP is accompanied by considerable survival benefit This finding is mainly coming from the retrospective analysis of observational clinical studies in CAP Results were also supported by the meta-analysis of these studies Superiority coming from the macrolide use is mainly shown in cases of severe CAP ie situations with pneumonia severity index PSI greater than 2 that are most commonly caused by Spneumoniae The proposed benefit of macrolides is coming from their anti-inflammatory mode of action This statement generates two main questions a what an anti-inflammatory mode of action consists of in the clinical setting and b is this a common property for all macrolides Although it is easy to suggest that an antimicrobial modulates immune responses in vitro it is extremely difficult to prove this in vivo The main hurdle is coming from the fact that it is difficult to decipher to what extent clinical benefit is coming from the antimicrobial effect per se and to what extent this is due to modulation of the immune responses In other terms an anti-inflammatory effect is better shown in infections caused by pathogens that do not belong to the antimicrobial spectrum of macrolides Our group has conducted two large scale randomized clinical trials RCTs where clarithromycin was co-administered intravenously along with β-lactams in either patients with ventilator-associated pneumonia VAP by multidrug-resistant Gram-negative pathogens or patients with severe Gram-negative infections like acute pyelonephritis intraabdominal infections and primary Gram-negative bacteremia The total number of patients enrolled in both studies was 800 and isolated pathogens did not belong to the antimicrobial spectrum of macrolides Addition of clarithromycin provided overall survival benefit after 90-days in patients with VAP 57 survival versus 40 of placebo-treated comparators Mortality by septic shock after 28-days was also considerably decreased in patients with severe Gram-negative infections 531 versus 731 of the comparators
Although these findings point towards an anti-inflammatory mode of action of clarithromycin they do not necessarily imply that a survival benefit similar to Gram-negative infections will apply in CAP There is only one RCT to test the anti-inflammatory effect of clarithromycin in patients with CAP This RCT was designed for non-inferiority and randomized patients were allocated into single β-lactam treatment or the combination with oral clarithromycin The primary endpoint was clinical instability after seven days Contrary to what investigators were expecting this was shown in 412 of non-macrolide treated patients and 336 of macrolide-treated patients p 0070 It may be argued that if the study was powered for superiority the study primary endpoint would have shown benefit from the addition of clarithromycin
In recent publication coming from the research network of the Hellenic Sepsis Study Group HSSG 130 patients with CAP were treated with a combination of β-lactam and clarithromycin They were compared with another 130 patients treated with a combination of β-lactam and azithromycin with 130 patients treated with respiratory fluoroquinolone monotherapy and with 130 treated with β-lactam monotherapy The study has a case-matching design and selection of cases of the three comparator groups were based on the group of patients treated with clarithromycin Matching selection criteria were severity as assessed by the severity score of SOFA sequential organ failure assessment APACHE II acute physiology and chronic health evaluation PSI and CCI Charlsons comorbidity index and type of β-lactam The 28-day mortality of the four groups was 208 338 323 and 362 respectively showing a profound survival benefit with the intake of clarithromycin
Based on the above analysis it seems likely that an RCT that proves the attenuation of the high inflammatory burden of the host with CAP after addition of clarithromycin in the treatment regimen is missing The need for this RCT is outscored in the recent guidelines of ATS Such a type of RCT should take into consideration the SOFA score of the patients the presence of the systemic inflammatory response syndrome SIRS the existence of elevated procalcitonin PCT in serum and the outcome of patients infected by macrolide-resistant Spneumoniae SOFA score is nowadays proposed as the sine qua non for severity PCT more than 025 ngml is widely accepted as an index of systemic inflammation in the event of CAP to such an extent that decrease more than 80 or to levels lower than 025 ngml can be used as an index of therapy withdrawal In such an RCT rapid resolution of the high inflammatory burden of the host should be highlighted in the achievement of the early treatment response of CAP after 72 hours that is recently appointed by the Food and Drug Administration and the European Medicines Agency as the primary endpoint goal of CAP
This is an RCT that is aiming to prove that addition of oral clarithromycin to a β-lactam rapidly attenuates the high inflammatory burden of the host in CAP
The shift in the position of ATS expressed in the 2019 guidelines is coming from the growing body of evidence that the addition of a macrolide in the treatment regimen of CAP is accompanied by considerable survival benefit This finding is mainly coming from the retrospective analysis of observational clinical studies in CAP Results were also supported by the meta-analysis of these studies Superiority coming from the macrolide use is mainly shown in cases of severe CAP ie situations with pneumonia severity index PSI greater than 2 that are most commonly caused by Spneumoniae The proposed benefit of macrolides is coming from their anti-inflammatory mode of action This statement generates two main questions a what an anti-inflammatory mode of action consists of in the clinical setting and b is this a common property for all macrolides Although it is easy to suggest that an antimicrobial modulates immune responses in vitro it is extremely difficult to prove this in vivo The main hurdle is coming from the fact that it is difficult to decipher to what extent clinical benefit is coming from the antimicrobial effect per se and to what extent this is due to modulation of the immune responses In other terms an anti-inflammatory effect is better shown in infections caused by pathogens that do not belong to the antimicrobial spectrum of macrolides Our group has conducted two large scale randomized clinical trials RCTs where clarithromycin was co-administered intravenously along with β-lactams in either patients with ventilator-associated pneumonia VAP by multidrug-resistant Gram-negative pathogens or patients with severe Gram-negative infections like acute pyelonephritis intraabdominal infections and primary Gram-negative bacteremia The total number of patients enrolled in both studies was 800 and isolated pathogens did not belong to the antimicrobial spectrum of macrolides Addition of clarithromycin provided overall survival benefit after 90-days in patients with VAP 57 survival versus 40 of placebo-treated comparators Mortality by septic shock after 28-days was also considerably decreased in patients with severe Gram-negative infections 531 versus 731 of the comparators
Although these findings point towards an anti-inflammatory mode of action of clarithromycin they do not necessarily imply that a survival benefit similar to Gram-negative infections will apply in CAP There is only one RCT to test the anti-inflammatory effect of clarithromycin in patients with CAP This RCT was designed for non-inferiority and randomized patients were allocated into single β-lactam treatment or the combination with oral clarithromycin The primary endpoint was clinical instability after seven days Contrary to what investigators were expecting this was shown in 412 of non-macrolide treated patients and 336 of macrolide-treated patients p 0070 It may be argued that if the study was powered for superiority the study primary endpoint would have shown benefit from the addition of clarithromycin
In recent publication coming from the research network of the Hellenic Sepsis Study Group HSSG 130 patients with CAP were treated with a combination of β-lactam and clarithromycin They were compared with another 130 patients treated with a combination of β-lactam and azithromycin with 130 patients treated with respiratory fluoroquinolone monotherapy and with 130 treated with β-lactam monotherapy The study has a case-matching design and selection of cases of the three comparator groups were based on the group of patients treated with clarithromycin Matching selection criteria were severity as assessed by the severity score of SOFA sequential organ failure assessment APACHE II acute physiology and chronic health evaluation PSI and CCI Charlsons comorbidity index and type of β-lactam The 28-day mortality of the four groups was 208 338 323 and 362 respectively showing a profound survival benefit with the intake of clarithromycin
Based on the above analysis it seems likely that an RCT that proves the attenuation of the high inflammatory burden of the host with CAP after addition of clarithromycin in the treatment regimen is missing The need for this RCT is outscored in the recent guidelines of ATS Such a type of RCT should take into consideration the SOFA score of the patients the presence of the systemic inflammatory response syndrome SIRS the existence of elevated procalcitonin PCT in serum and the outcome of patients infected by macrolide-resistant Spneumoniae SOFA score is nowadays proposed as the sine qua non for severity PCT more than 025 ngml is widely accepted as an index of systemic inflammation in the event of CAP to such an extent that decrease more than 80 or to levels lower than 025 ngml can be used as an index of therapy withdrawal In such an RCT rapid resolution of the high inflammatory burden of the host should be highlighted in the achievement of the early treatment response of CAP after 72 hours that is recently appointed by the Food and Drug Administration and the European Medicines Agency as the primary endpoint goal of CAP
This is an RCT that is aiming to prove that addition of oral clarithromycin to a β-lactam rapidly attenuates the high inflammatory burden of the host in CAP
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2020-004452-15 | EUDRACT_NUMBER | None | None |