Ignite Creation Date:
2024-05-06 @ 8:12 PM
Last Modification Date:
2024-10-26 @ 3:22 PM
Study NCT ID:
NCT06294600
Status:
RECRUITING
Last Update Posted:
2024-06-26
First Post:
2024-02-28
Brief Title:
Clarithromycin Treatment to Prevent Sepsis Progression in CAP REACT
Sponsor:
Hellenic Institute for the Study of Sepsis
Organization:
Hellenic Institute for the Study of Sepsis
Study Overview
Official Title:
Biomarker-Guided Early Elarithromycin Treatment to Prevent Sepsis Progression in Community-Acquired Pneumonia The React Randomized Clinical Trial
Status:
RECRUITING
Status Verified Date:
2024-02
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:
REACT
Brief Summary:
The primary objective of the REACT randomized clinical trial RCT is to optimize the clinical benefit from adjunctive clarithromycin treatment shown in the ACCESS trial and to provide evidence for the clinical benefit of early start of adjunctive oral clarithromycin guided by suPAR to prevent the progression into sepsis in patients with community-acquired pneumonia CAP at risk This can be achieved by endpoints incorporating clinical benefit with the effect of treatment on the improvement of the immune dysregulation of CAP The secondary objectives of REACT are to investigate the impact of early adjunctive treatment with clarithromycin on the resolution of CAP at the test-of-cure TOC visit
Detailed Description:
Sepsis is recognized nowadays as one of the major causes of global morbidity and mortality One analysis of global data revealed that 49 million of new cases are admitted to hospitals every year and that 11 million of the patients die Sepsis is the life-threatening organ dysfunction which develops due to the dysregulated response of the host to an infection mortality is ranging between 20 and 25 The most common infections leading to sepsis are infections of the lower respiratory tract LRTIs mainly community-acquired pneumonia CAP
Numerous attempts have been done the last decades to decrease the substantial mortality of sepsis Standard-of-care SoC therapy for sepsis is framed by the Surviving Sepsis Campaign SSC guidelines which are published every four years since 2004 last publication 2021 The backbone of these guidelines is the early administration of intravenous antibiotics and fluids In all editions of the SSC guidelines early means less than one hour from sepsis recognition The experts recognize that the secret to decrease mortality is to intervene early before the dysregulated host response to the infection becomes exaggerated and impossible to withhold The experts state that for every hour of delay in intervention the odds for survival decrease by relative 76 Then the real ambiguity moves on how the initiation of the sepsis process can be recognized earlier than clinical deterioration appears
The only way to achieve our current strategy is to implement a strategy linking the increase of a biomarker to an early intervention This biomarker can be either a measured circulating protein or a bioscore An example of how this strategy works is the biomarker-guided treatment of early COVID-19 coronavirus disease 2019 recently approved by the European Medicines Agency EMA The biomarker suPAR soluble urokinase plasminogen activator receptor was used as a tool to recognize the patient at risk for severe respiratory failure and guided the start of the drug anakinra This led to an overall 64 clinical benefit so as to become the first early precision intervention approved for infections by the EMA The registered cut-off of suPAR which guides early intervention is 6 ngml or more
The suPAR assay is not commercially available in the United States However all enrolled patients in SAVE-MORE trial were required to have a plasma soluble urokinase plasminogen activator receptor suPAR level 6 ngmL SAVE-MORE was double-blind randomized controlled trial evaluated the efficacy and safety of anakinra an IL-1αβ inhibitor in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR 6 ng ml-1 859 n 510 of whom were receiving dexamethasone In order to identify a comparable population as was studied in the SAVE-MORE trial an alternative patient identification method was developed by the Food and Drug Administration FDA of the United States to select patients most likely to have suPAR 6 ngmL based on commonly measured patient characteristics Appendix I This score contains eight clinical variable and patients meeting at least 3 of the variables should receive early anakinra treatment Patients meeting at least three of the following eight criteria are considered likely to have suPAR 6 ngmL at baseline i age 75 years or more ii need for oxygen supplementation iii currentprevious smoking status iv Sequential Organ Failure Assessment SOFA score 3 or more v neutrophil-to-lymphocyte ratio NLR 7 or more vi blood hemoglobin 105 gdL or less vii medical history of ischemic stroke and viii blood urea 50 mgdL or more andor medical history of renal disease According to the SmPC suPAR is a biomarker is used at the Emergency Department ED for the triage of patients for early discharge home or not levels exceeding 6ngml advise for hosptialization
With this precision-embedded approach adjunctive treatments may attenuate the exaggerated response of the host and improve outcomes Macrolides are a unique class of drugs that combine both antibiotic and anti-inflammatory properties Several meta-analyses have proven that addition of a macrolide to treatment decreases mortality by community-acquired pneumonia CAP However the mortality benefit from macrolides treatment is coming from meta-analyses and no randomized clinical trial RCT has been published so far to demonstrate such a benefit This is also heavily criticized in the recently published guidelines by the European Society of Intensive Care with the European Society of Clinical Microbiology and Infections Diseases ESCMID for the management of severe CAP where the recommendation for the co-administration of macrolides to β-lactams is characterized as low-quality evidence
The only available RCT testing the value of early intervention with macrolides in patients with community-acquired pneumonia CAP is ACCESS A randomized clinical trial of oral Clarithromycin in Community-acquired pneumonia to attenuatE inflammatory responseS and improve outcomeS EudraCT number 2020-004452-15 ClinicalTrialsgov NCT04724044 The inclusion criteria of the ACCESS trial have the characteristics of precision therapy ie participants were adults with CAP meeting at least two of the criteria of the systemic inflammatory response syndrome with SOFA sequential organ failure assessment score 2 or more and circulating procalcitonin 025 ngml or more ACCESS had a composite primary endpoint pointing towards an early anti-inflammatory clinical benefit of clarithromycin Patients achieving the endpoint should meet both two conditions A and B by day 4 since start of the study drug condition A defined as at least 50 decrease of the respiratory symptoms score RSS and condition B defined as at least 30 decrease of the baseline SOFA score andor favorable PCT kinetics defined as at least 80 decrease of the baseline PCT or PCT less than 025 ngml The study succeeded in the primary endpoint since this was met in 383 of patients randomized to the SoC placebo group and in 679 of patients randomized to the SoC clarithromycin group p00001 The ACCESS study also showed remarkable efficacy in all secondary endpoints and mainly to those endpoints pointing towards prevention of sepsis progression
1130 of patients treated with SoC and placebo progressed into sepsis during the 28-day follow-up compared to only 225 of patients treated with oral clarithromycin and placebo hazard ratio 019 p 0009 278 of patients treated with SoC and placebo developed a new sepsis episode during the 28-day follow-up compared to only 148 of patients treated with oral clarithromycin and placebo hazard ratio 048 p 0009 and 654 of patients treated with SoC and placebo were discharged from hospital alive compared to 784 of patients treated with oral clarithromycin and placebo hazard ratio 138 p 0027 Post-hoc analysis showed that 874 of study participants were meeting at least 3 of the FDA clinical score making the participants at high likelihood for suPAR 6 ngml or more This means that use of suPAR can discriminate early patients with CAP who are at high likelihood to receive benefit towards prevention of progression into sepsis and organ dysfunction through early start of clarithromycin treatment
Data from the ACCESS study also showed a significant effect of clarithromycin treatment on modulation of immune dysregulation taking place in CAP by day 4 when the primary endpoint was met These data points towards improvement of the function of circulating monocytes towards better production of TNFα tumour necrosis factor-alpha after stimulation decrease of circulating interleukin IL-10 and improvement of the IL-8IL-10 ratio
Numerous attempts have been done the last decades to decrease the substantial mortality of sepsis Standard-of-care SoC therapy for sepsis is framed by the Surviving Sepsis Campaign SSC guidelines which are published every four years since 2004 last publication 2021 The backbone of these guidelines is the early administration of intravenous antibiotics and fluids In all editions of the SSC guidelines early means less than one hour from sepsis recognition The experts recognize that the secret to decrease mortality is to intervene early before the dysregulated host response to the infection becomes exaggerated and impossible to withhold The experts state that for every hour of delay in intervention the odds for survival decrease by relative 76 Then the real ambiguity moves on how the initiation of the sepsis process can be recognized earlier than clinical deterioration appears
The only way to achieve our current strategy is to implement a strategy linking the increase of a biomarker to an early intervention This biomarker can be either a measured circulating protein or a bioscore An example of how this strategy works is the biomarker-guided treatment of early COVID-19 coronavirus disease 2019 recently approved by the European Medicines Agency EMA The biomarker suPAR soluble urokinase plasminogen activator receptor was used as a tool to recognize the patient at risk for severe respiratory failure and guided the start of the drug anakinra This led to an overall 64 clinical benefit so as to become the first early precision intervention approved for infections by the EMA The registered cut-off of suPAR which guides early intervention is 6 ngml or more
The suPAR assay is not commercially available in the United States However all enrolled patients in SAVE-MORE trial were required to have a plasma soluble urokinase plasminogen activator receptor suPAR level 6 ngmL SAVE-MORE was double-blind randomized controlled trial evaluated the efficacy and safety of anakinra an IL-1αβ inhibitor in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR 6 ng ml-1 859 n 510 of whom were receiving dexamethasone In order to identify a comparable population as was studied in the SAVE-MORE trial an alternative patient identification method was developed by the Food and Drug Administration FDA of the United States to select patients most likely to have suPAR 6 ngmL based on commonly measured patient characteristics Appendix I This score contains eight clinical variable and patients meeting at least 3 of the variables should receive early anakinra treatment Patients meeting at least three of the following eight criteria are considered likely to have suPAR 6 ngmL at baseline i age 75 years or more ii need for oxygen supplementation iii currentprevious smoking status iv Sequential Organ Failure Assessment SOFA score 3 or more v neutrophil-to-lymphocyte ratio NLR 7 or more vi blood hemoglobin 105 gdL or less vii medical history of ischemic stroke and viii blood urea 50 mgdL or more andor medical history of renal disease According to the SmPC suPAR is a biomarker is used at the Emergency Department ED for the triage of patients for early discharge home or not levels exceeding 6ngml advise for hosptialization
With this precision-embedded approach adjunctive treatments may attenuate the exaggerated response of the host and improve outcomes Macrolides are a unique class of drugs that combine both antibiotic and anti-inflammatory properties Several meta-analyses have proven that addition of a macrolide to treatment decreases mortality by community-acquired pneumonia CAP However the mortality benefit from macrolides treatment is coming from meta-analyses and no randomized clinical trial RCT has been published so far to demonstrate such a benefit This is also heavily criticized in the recently published guidelines by the European Society of Intensive Care with the European Society of Clinical Microbiology and Infections Diseases ESCMID for the management of severe CAP where the recommendation for the co-administration of macrolides to β-lactams is characterized as low-quality evidence
The only available RCT testing the value of early intervention with macrolides in patients with community-acquired pneumonia CAP is ACCESS A randomized clinical trial of oral Clarithromycin in Community-acquired pneumonia to attenuatE inflammatory responseS and improve outcomeS EudraCT number 2020-004452-15 ClinicalTrialsgov NCT04724044 The inclusion criteria of the ACCESS trial have the characteristics of precision therapy ie participants were adults with CAP meeting at least two of the criteria of the systemic inflammatory response syndrome with SOFA sequential organ failure assessment score 2 or more and circulating procalcitonin 025 ngml or more ACCESS had a composite primary endpoint pointing towards an early anti-inflammatory clinical benefit of clarithromycin Patients achieving the endpoint should meet both two conditions A and B by day 4 since start of the study drug condition A defined as at least 50 decrease of the respiratory symptoms score RSS and condition B defined as at least 30 decrease of the baseline SOFA score andor favorable PCT kinetics defined as at least 80 decrease of the baseline PCT or PCT less than 025 ngml The study succeeded in the primary endpoint since this was met in 383 of patients randomized to the SoC placebo group and in 679 of patients randomized to the SoC clarithromycin group p00001 The ACCESS study also showed remarkable efficacy in all secondary endpoints and mainly to those endpoints pointing towards prevention of sepsis progression
1130 of patients treated with SoC and placebo progressed into sepsis during the 28-day follow-up compared to only 225 of patients treated with oral clarithromycin and placebo hazard ratio 019 p 0009 278 of patients treated with SoC and placebo developed a new sepsis episode during the 28-day follow-up compared to only 148 of patients treated with oral clarithromycin and placebo hazard ratio 048 p 0009 and 654 of patients treated with SoC and placebo were discharged from hospital alive compared to 784 of patients treated with oral clarithromycin and placebo hazard ratio 138 p 0027 Post-hoc analysis showed that 874 of study participants were meeting at least 3 of the FDA clinical score making the participants at high likelihood for suPAR 6 ngml or more This means that use of suPAR can discriminate early patients with CAP who are at high likelihood to receive benefit towards prevention of progression into sepsis and organ dysfunction through early start of clarithromycin treatment
Data from the ACCESS study also showed a significant effect of clarithromycin treatment on modulation of immune dysregulation taking place in CAP by day 4 when the primary endpoint was met These data points towards improvement of the function of circulating monocytes towards better production of TNFα tumour necrosis factor-alpha after stimulation decrease of circulating interleukin IL-10 and improvement of the IL-8IL-10 ratio
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?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2023-507295-40 | EUDRACT_NUMBER | None | None |