SepsisPhase 3NCT05443854
Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: (Combination-Lock01)
A Phase 3 study testing Aminoglycosides intervention, Lack of protective isolation intervention and No systematic aminoglycosides intervention - standard arm in people with Sepsis and Septic Shock, run by Assistance Publique - Hôpitaux de Paris.
Trial summary
Sepsis remains the leading cause of ICU admission in neutropenic patients. This condition remains associated with a high morbidity and mortality, with hospital mortality of 60% when vasopressors are required. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Septic Shock, Hematologic Malignancy
- What is being tested?
- Aminoglycosides intervention, Lack of protective isolation intervention and No systematic aminoglycosides intervention - standard arm
- Type of treatment
- Injection or infusion, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 340 participants
- Where
- No sites listed yet
- Study dates
- Sep 2022to Jun 2024
- Phase
- Phase 3
- 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
- Sepsis or septic shock as defined by SEPSIS3 definition
- Underlying tumor, allogeneic stem cell transplantation or hematological malignancy
- Neutropenia (defined by either absolute neutrophil count <500/mm3 or leucocytes <1000/mm3) related to an underlying malignancy or its treatment
- Informed or deferred consent
Who cannot join
- Pregnancy and breastfeeding
- Moribund patients (death expected within 48 hours by attending physician)
- Previous participation to this study
- No affiliation to social security
- Patients under legal protection according to French Law
- Patient having received more than 1 injection of aminoglycosides in the 3 days preceding ICU admission
Show all 11Show fewer
- Contraindication to aminoglycosides as mentioned in SpC section 4.3:
- Hypersensitivity to amikacin, to other antibiotics from the aminoglycoside family, or to any excipient from the amikacin used.
- Patients with documented allergy to aminoglycosides
- Myasthenia gravis
- Concomitant administration of intravenous Polymyxin- Delay between admission for a new sepsis and inclusion>24 hours or (in patients previously admitted in the ICU for another reason) delay between new sepsis in study inclusion >24h
Trial locations and contacts
No sites are listed yet.
About this study
Official title: Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: A Randomized 2 by 2 Factorial Design Randomized Pragmatic Trial.
Sepsis remains the leading cause of ICU admission in neutropenic patients. This condition remains associated with a high morbidity and mortality, with hospital mortality of 60% when vasopressors are required.
Full protective isolation (including geographic isolation, technical isolation, high-efficiency air filtration, and digestive decontamination) proved to be efficient in patients with profound and prolonged neutropenia with regard to infection rate. However, these studies are biased and were performed up to 40 years ago. More recent studies, performed in patients with less profound neutropenia, or performed without digestive decontamination or with partial protective isolation led however to negative results. More importantly, isolation has been demonstrated to limit access to patients' room and to be associated with suboptimal monitoring, with increased rate of severe and avoidable adverse events. This may explain the uneven use of protective isolation in hematology ward and expert's suggestion to appraise protective isolation benefits using large well conducted RCT.
Read more
In neutropenic patients with suspected sepsis, urgent broad antibiotic therapy is mandatory and failure to initiate adequate antibiotic therapy within 1 hour has been associated with a 10 fold increase in adjusted mortality. Current IDSA guidelines recommend using preferentially large anti-pseudomonas beta-lactam therapy. Routine antibiotic combination using aminoglycosides is controversial and not recommended. On one hand, meta-analyses suggested not-only a lack of benefit from this association but also increased rate of renal failure and a trend towards a higher mortality rate with aminoglycosides use. On the other hand, subgroup analysis and low-level evidences studies suggest however a benefit from aminoglycosides in critically-ill patients, patients with severe sepsis, or those with documented gram negative infection. Along this line, both the recent Cochran systematic review and the recent French guidelines focusing on neutropenia management in critically-ill patients advocated additional trials in this field focusing in the sickest patients.
The current study aims to assess benefits of protective isolation and systematic use of aminoglycosides combination antibiotic therapy in critically-ill patients with cancer-related neutropenia and sepsis or septic shock. To do so, the investigators intend to perform a 2x2 factorial design randomized pragmatic trial comparing on one hand benefits of protective isolation (versus no protective isolation) and in the other hand benefits of systematic aminoglycosides antibiotics combination (versus no systematic combination).
- Being tested
- Aminoglycosides intervention, Lack of protective isolation intervention, No systematic aminoglycosides intervention - standard arm, Protective isolation intervention - standard arm
- Medical subject headings
- Sepsis, Shock, Septic, Hematologic Neoplasms, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Aminoglycosides interventionDrug
Antibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines [3, 28, 50].
Systematic aminoglycoside therapy using Amikacin at a dose of 25 to 30 mg/Kg per dose, at a rate of a maximum of 1 infusion per day will be delivered.
Recommended duration will be of three days or until microbiological documentation.
Lack of protective isolation interventionBehavioural
Protective isolation will be avoided until ICU discharge is deemed possible. Specific measures regarding nutrition (including avoidance of food consider at risk of fungal contamination) and water protection will be maintained.
Extended universal hygiene measures will be maintained and use of mask will be advocated during viral epidemic periods.
A high degree of compliance as regard to antifungal prophylaxis guidelines and local standard hygiene procedures will be advocated
No systematic aminoglycosides intervention - standard armOther
Antibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines [3, 28, 50].
No systematic aminoglycoside therapy will be provided except in presence of predefined specific organ infection (such intra-vascular infection such endocarditis for example) or drug-resistant infection requiring aminoglycosides.
Protective isolation intervention - standard armOther
Protective isolation will be provided systematically as currently practiced in participating centers. Modality will be in line with recent SRLF guidelines, we will recommend for the patients to receive an isolation the maximal available isolation with the aim to provide:
- High-efficiency air filtration [filtration of 99.7% of particles greater than or equal to 0.3 µm; International Organization for Standardization (ISO) class 5 or better]
- Geographical isolation in an individual room
- Technical isolation, including a face mask and a cap. This approach of isolation will however be pragmatic on the basis of the "best available" level of isolation in line with recommendation, while not delaying ICU admission and patients' care
| Study group | Role | What they receive |
|---|---|---|
| Aminoglycosides intervention | Experimental | Systematic aminoglycoside therapy using Amikacin at a dose of 25 to 30 mg/Kg per dose, at a rate of a maximum of 1 infusion per day will be delivered.
Recommended duration will be of three days or until microbiological documentation. Receives: Drug: Aminoglycosides intervention |
| Lack of protective isolation intervention | Experimental | Protective isolation will be avoided until ICU discharge is deemed possible. Specific measures regarding nutrition (including avoidance of food consider at risk of fungal contamination) and water protection will be maintained. Receives: Behavioral: Lack of protective isolation intervention |
| No systematic aminoglycosides intervention | Other | Antibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines - standard arm Receives: Other: No systematic aminoglycosides intervention - standard arm |
| Protective isolation intervention | Other | Protective isolation will be provided systematically as currently practiced in participating centers - standard arm Receives: Other: Protective isolation intervention - standard arm |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Overall death
Measured: at day 90
Secondary outcomes (21)
Mortality
Overall death
Measured: at Day-28
Hospital mortality
Mortality at hospital discharge
Measured: at hospital discharge within 3 months
Incidence of acute kidney injury
Acute kidney injury (AKI) will be defined according to KDIGO criteria
Measured: within 3 months
Severity of acute kidney injury
Acute kidney injury (AKI) will be defined according to KDIGO criteria
Measured: within 3 months
Duration of acute kidney injury
Acute kidney injury (AKI) will be defined according to KDIGO criteria
Measured: within 3 months
Major Adverse Kidney Events
Measured: at day-28
Major Adverse Kidney Events
Measured: at day 90
Incidence of clinically apparent loss of hearing
Measured: at ICU discharge
Incidence of clinically apparent loss of hearing
Measured: at dat 90
Rate of adherence of hand hygiene
hand hygiene will be assessed by external observer
Measured: at 24 hours
Incidence density of selected serious adverse events
Measured: within 3 months
Incidence density of new bacterial episodes
Measured: within 3 months
Incidence density of new viral infection episodes
Measured: within 3 months
Incidence density of new fungal episodes
Measured: within 3 months
Number of days free from organ support therapy (mechanical ventilation, vasopressors or RRT)
Measured: at day 28
Rate of clinical cure
Measured: within 3 months
Frequency of initial antibiotic therapy inadequate as regard to microbiological documentation.
Measured: at inclusion
Number of day free of antibiotic therapy
Measured: at day-28
Duration of aminoglycoside therapy
Measured: within 3 months
Rate of aminoglycoside overdosage according to residual concentration
Measured: within 3 months
Rate of overuse when compared to experts recommendations
Measured: within 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jul 2022
- Study startSep 2022 (estimated)
- Primary completionJun 2024 (estimated)
- Study completionJun 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 340 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05443854
- Sponsor's protocol ID
- APHP180690
- Status last verified
- Jun 2022
- First submitted
- 17 Jun 2022
- Last updated
- 5 Jul 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 5 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: A Randomized 2 by 2 Factorial Design Randomized Pragmatic Trial.
- ClinicalTrials.gov ID
- NCT05443854
- Acronym / sponsor ID
- APHP180690
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 340 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- Sep 2022 (estimated)
- Primary completion
- Jun 2024 (estimated)
- Study completion
- Jun 2024 (estimated)
- First posted
- 5 Jul 2022 (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.
Sepsis remains the leading cause of ICU admission in neutropenic patients. This condition remains associated with a high morbidity and mortality, with hospital mortality of 60% when vasopressors are required.
Full protective isolation (including geographic isolation, technical isolation, high-efficiency air filtration, and digestive decontamination) proved to be efficient in patients with profound and prolonged neutropenia with regard to infection rate. However, these studies are biased and were performed up to 40 years ago. More recent studies, performed in patients with less profound neutropenia, or performed without digestive decontamination or with partial protective isolation led however to negative results. More importantly, isolation has been demonstrated to limit access to patients' room and to be associated with suboptimal monitoring, with increased rate of severe and avoidable adverse events. This may explain the uneven use of protective isolation in hematology ward and expert's suggestion to appraise protective isolation benefits using large well conducted RCT.
In neutropenic patients with suspected sepsis, urgent broad antibiotic therapy is mandatory and failure to initiate adequate antibiotic therapy within 1 hour has been associated with a 10 fold increase in adjusted mortality. Current IDSA guidelines recommend using preferentially large anti-pseudomonas beta-lactam therapy. Routine antibiotic combination using aminoglycosides is controversial and not recommended. On one hand, meta-analyses suggested not-only a lack of benefit from this association but also increased rate of renal failure and a trend towards a higher mortality rate with aminoglycosides use. On the other hand, subgroup analysis and low-level evidences studies suggest however a benefit from aminoglycosides in critically-ill patients, patients with severe sepsis, or those with documented gram negative infection. Along this line, both the recent Cochran systematic review and the recent French guidelines focusing on neutropenia management in critically-ill patients advocated additional trials in this field focusing in the sickest patients.
The current study aims to assess benefits of protective isolation and systematic use of aminoglycosides combination antibiotic therapy in critically-ill patients with cancer-related neutropenia and sepsis or septic shock. To do so, the investigators intend to perform a 2x2 factorial design randomized pragmatic trial comparing on one hand benefits of protective isolation (versus no protective isolation) and in the other hand benefits of systematic aminoglycosides antibiotics combination (versus no systematic combination).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Aminoglycosides intervention | Experimental | Drug: Aminoglycosides interventionSystematic aminoglycoside therapy using Amikacin at a dose of 25 to 30 mg/Kg per dose, at a rate of a maximum of 1 infusion per day will be delivered. Recommended duration will be of three days or until microbiological documentation. |
| Lack of protective isolation intervention | Experimental | Behavioral: Lack of protective isolation interventionProtective isolation will be avoided until ICU discharge is deemed possible. Specific measures regarding nutrition (including avoidance of food consider at risk of fungal contamination) and water protection will be maintained. |
| No systematic aminoglycosides intervention | Other | Other: No systematic aminoglycosides intervention - standard armAntibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines - standard arm |
| Protective isolation intervention | Other | Other: Protective isolation intervention - standard armProtective isolation will be provided systematically as currently practiced in participating centers - standard arm |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age ≥ 18 years
- Sepsis or septic shock as defined by SEPSIS3 definition
- Underlying tumor, allogeneic stem cell transplantation or hematological malignancy
- Neutropenia (defined by either absolute neutrophil count <500/mm3 or leucocytes <1000/mm3) related to an underlying malignancy or its treatment
- Informed or deferred consent
Key exclusion criteria (11 listed)
- Pregnancy and breastfeeding
- Moribund patients (death expected within 48 hours by attending physician)
- Previous participation to this study
- No affiliation to social security
- Patients under legal protection according to French Law
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 |
|---|---|---|
| Aminoglycosides interventionAntibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines [3, 28, 50]. Systematic aminoglycoside therapy using Amikacin at a dose of 25 to 30 mg/Kg per dose, at a rate of a maximum of 1 infusion per day will be delivered. Recommended duration will be of three days or until microbiological documentation. | Drug | Aminoglycosides intervention |
| Lack of protective isolation interventionProtective isolation will be avoided until ICU discharge is deemed possible. Specific measures regarding nutrition (including avoidance of food consider at risk of fungal contamination) and water protection will be maintained. Extended universal hygiene measures will be maintained and use of mask will be advocated during viral epidemic periods. A high degree of compliance as regard to antifungal prophylaxis guidelines and local standard hygiene procedures will be advocated | Behavioural | Lack of protective isolation intervention |
| No systematic aminoglycosides intervention - standard armAntibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines [3, 28, 50]. No systematic aminoglycoside therapy will be provided except in presence of predefined specific organ infection (such intra-vascular infection such endocarditis for example) or drug-resistant infection requiring aminoglycosides. | Other | No systematic aminoglycosides intervention |
| Protective isolation intervention - standard armProtective isolation will be provided systematically as currently practiced in participating centers. Modality will be in line with recent SRLF guidelines, we will recommend for the patients to receive an isolation the maximal available isolation with the aim to provide: 1. High-efficiency air filtration [filtration of 99.7% of particles greater than or equal to 0.3 µm; International Organization for Standardization (ISO) class 5 or better] 2. Geographical isolation in an individual room 3. Technical isolation, including a face mask and a cap. This approach of isolation will however be pragmatic on the basis of the "best available" level of isolation in line with recommendation, while not delaying ICU admission and patients' care | Other | Protective isolation intervention |
Primary outcome
Mortality
Time frame: at day 90
Overall death
21 secondary outcomes
Mortality
Time frame: at Day-28
Hospital mortality
Time frame: at hospital discharge within 3 months
Incidence of acute kidney injury
Time frame: within 3 months
Severity of acute kidney injury
Time frame: within 3 months
Duration of acute kidney injury
Time frame: within 3 months
Major Adverse Kidney Events
Time frame: at day-28
Major Adverse Kidney Events
Time frame: at day 90
Incidence of clinically apparent loss of hearing
Time frame: at ICU discharge
Incidence of clinically apparent loss of hearing
Time frame: at dat 90
Rate of adherence of hand hygiene
Time frame: at 24 hours
Incidence density of selected serious adverse events
Time frame: within 3 months
Incidence density of new bacterial episodes
Time frame: within 3 months
Incidence density of new viral infection episodes
Time frame: within 3 months
Incidence density of new fungal episodes
Time frame: within 3 months
Number of days free from organ support therapy (mechanical ventilation, vasopressors or RRT)
Time frame: at day 28
Rate of clinical cure
Time frame: within 3 months
Frequency of initial antibiotic therapy inadequate as regard to microbiological documentation.
Time frame: at inclusion
Number of day free of antibiotic therapy
Time frame: at day-28
Duration of aminoglycoside therapy
Time frame: within 3 months
Rate of aminoglycoside overdosage according to residual concentration
Time frame: within 3 months
Rate of overuse when compared to experts recommendations
Time frame: within 3 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jul 2022.
- Individual participant dataSharing planned: Undecided
Related trials for Sepsis
Not yet recruitingPhase 2/3
A Pivotal Safety and Immunogenicity GBS-NN/NN2 Vaccine Maternal Immunisation Trial
Streptococcus Agalactiae Infection, Neonatal Sepsis
Active, not recruiting
CT for Personalized Mechanical Ventilation
Ventilator-Induced Lung Injury, Sepsis Syndrome
RecruitingPhase 4
A Study to Compare the Efficacy and Safety of Extended and Intermittent Infusion of Beta-lactams in Critically Ill Paediatric Patients
Infection, Sepsis
Not yet recruiting
Double Plasma Separation and Adsorption in Acute-on-Chronic Liver Failure (DPMAS-ACLF Trial)
Acute-on-Chronic Liver Failure (ACLF)
Active, not recruitingPhase 4
Thymosin Alpha 1 and IgM Levels in Sepsis
Sepsis, Septic Shock
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.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Aminoglycosides intervention, Lack of protective isolation intervention and No systematic aminoglycosides intervention - standard arm in people with Sepsis and Septic Shock, run by Assistance Publique - Hôpitaux de Paris.
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 5 inclusion and 11 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: status not confirmed, as of the sponsor's last update on 5 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
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.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Michael Darmon (01 42 49 94 19, michael.darmon@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: at day 90). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 5 Jul 2022.