Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02852902 |
| Other study ID # |
REIPI-3.50 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2016 |
| Est. completion date |
January 1, 2018 |
Study information
| Verified date |
March 2019 |
| Source |
Spanish Network for Research in Infectious Diseases |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Main objective: to observationally assess the efficacy and safety of different antimicrobials
in BSI due to ESBL or carbapenemase-producing Enterobacterales in SOT.
Secondary objectives:
1. To evaluate the efficacy and safety of different antibiotics used for the treatment of
infections caused by ESBL- and carbapenemase-producing Enterobacterales in the SOT
population.
2. To compare the efficacy of different antimicrobials between SOT and non-SOT patients
(using matched controls from the "non-transplant" INCREMENT cohort).
3. To create a microbiological collection of ESBL- and carbapenemase-producing
Enterobacterales isolated from the SOT population.
4. To provide data on specific MICs for each antimicrobial evaluated.
5. To provide data on the prevalence of specific mechanisms of resistance and their
clinical impact in the particular setting of SOT.
6. To organise an international consortium capable of developing high quality prospective
cohort studies and randomised clinical trials in the area of MDR and XDR
Enterobacterales in SOT.
Description:
METHODS
Study design: multicentre, international retrospective cohort study.
Sites: multiple expert investigators from different countries will be invited. Criteria for
participation will include accessibility to a database with the required data or ability to
retrospectively collect the data in a timely manner.
Procedure Centers will receive by email a personal key for access to an electronic Case
Report File (CRF), on the official INCREMENT-SOT website at
http://www.increment-sotproject.org/
The participant centres will be requested to include:
- Previously published cases: all these cases should be included if possible. The fact
that the case was previously published should be specified in the database.
- Additionally, participants will be requested to include consecutive episodes detected by
reviewing their databases (clinical, infection control or microbiological records) from
January 2004 to October 2016, according to the following criteria:
- For ESBL producers: Consecutive cases for which the enzyme was characterised at
least to group level by PCR (it is, CTX-M, SHV, TEM) should be prioritised despite
the date of diagnosis. If PCR-characterisation was not performed, cases in which
ESBL-production was identified using a standard phenotypic method may be included.
- For carbapenemase-producers: cases in which the carbapenemase gene was detected by
a molecular method or the isolate showed an identical phenotype to previously
characterized carbapenemase-producers detected at the same site.
Overall, to avoid selection biases, consecutive cases according to previous criteria should
be included.
Variables
A common, online database has been designed. Access to this database will be restricted to
authorized researchers by use of an individual user name and password.
Main outcome variables: Cure rate at day 14 and all-cause mortality until day 30. For safety
issues, frequency and types of renal and liver toxicity.
Secondary outcome variables: Mortality at 72 hours, 7, 14 and 90 days, clinical improvement
at 72 hours, clinical cure at day 28. Renal and liver toxicity and other serious adverse
events.
Explanatory variables:
- Demographics
- Use of antibiotics within 30 days before the BSI.
- Severity of chronic underlying conditions: McCabe and Charlson index
- Acute severity of underlying disease: Pitt score during the day before BSI.
- Type of acquisition
- Source of BSI
- Severity of SIRS at presentation
- Microorganism, MICs, clinical category (Susceptible, Intermediate, Resistant), guideline
(CLSI or EUCAST), mechanisms of resistance if studied.
- Empirical therapy
- Definitive therapy
- Bacteremia Source Control: drainage within the first four days, removal of prosthetic
material, removal of infected catheter, etc.
- Renal function when bacteremia occurred (Creatinine clearance).
- Selective Intestinal Decontamination (SID) during the previous 12 months and type of SID
(drugs used).
- Variables related with transplantation:
- Type of SOT
- Day after transplantation
- Acute rejection within 30 days before the BSI
- Leukopenia (number of lymphocytes, lymphocyte subpopulations, immunoglobulins and
complement).
- Basal immunosuppression
- Induction of immunosuppression
- Prophylaxis with TMP/SMX within 30 days before the BSI
- Surgical reoperation.
- Urinary catheter.
- Urinary stenosis (renal)
- Biliary stenosis (liver)
- Traqueal stenosis (lung)
- Post-transplant dialysis within 30 days before the BSI
- CMV replication within 30 days before the BSI
- CMV disease within 30 days before the BSI
- Mechanical ventilation
- Other underlining condition
Definitions
- Clinically significant bacteremia: bacteremia that occurs in a patient who fulfils
criteria for systemic inflammatory response (see below, sepsis criteria).
- Charlson index: punctuation is automatically calculated by filling the data in the
database. Alternatively, if Pitt score was previously calculated, it may be added
directly to the database. For all diseases, a medical diagnosis in chart is enough.
Additionally, the following criteria should be used: 1,Diabetes mellitus: antidiabetic
therapy (oral or insulin); 2, Chronic pulmonary disease: any disease leading to chronic
respiratory insufficiency; 3,Myocardial infarction: EKG evidence; 4, Congestive heart
failure: NYHA grade II or higher; 5, Peripheral arterial disease: when causing skin
ulcer or the need for revascularization or amputation; 6. Dementia: if significantly
limiting independence for basic activities; 7,Connective tissue disease: if requiring
immunosuppressive therapy, 8.Liver disease: chronic hepatitis, significant liver
fibrosis or cirrhosis; 9,Kidney disease: creatinine clearance <30 ml/min or the need for
chromic dialysis; 10 Any tumour: any malignancy requiring chemotherapy and/or
radiotherapy or palliative care.
- McCabe classification (modified). This is a classification for the chronic underlying
condition (not the acute condition): non-fatal underlying disease (no underlying disease
or related death is expected to occur in the next 5 years), ultimately fatal underlying
disease (related death is expected to occur in the next 5 years), or rapidly fatal
disease (related death is expected to occur in the next year).
- Pitt score: punctuation is automatically calculated by filling the data in the database,
which should be retrospectively collected in the 24 hours prior to diagnosis of
bacteremia. Alternatively, if Pitt score had been calculated previously, it can be
directly added.
- SIRS severity
- Sepsis: at least 2 of the following: temperature >38ºC or <36ºC, respiratory rate
>20 or PaCO2 <32 mmHg, heart rate >90, altered mental status, systolic blood
pressure <90 mmHg, leukocyte count >12.000/mm3 or <4,000/mm3 or immature forms
>10%.
- Severe sepsis: sepsis plus one of the following: hypotension (systolic BP <90 mmHg,
median BP <70 mmHg, decrease in median BO >40 mmGh), organ dysfunction
(respiratory, renal, liver, neurologic, hematologic), or hyperlactatemia (> 3
mmol/L)
- Septic shock: sustained hypotension not responding to fluid support therapy and
requiring inotropic support.
- Acquisition. Nosocomial if infection signs/symptoms started >48 hours after hospital
admission or in less than 48 hours after hospital discharge. Otherwise, the case should
be considered community-onset.
o If community-onset, the episode is considered healthcare-associated if fulfilling any
of the following criteria in the previous 3 months: hospitalization in acute care
center, any kind of dialysis, surgery, specialized home care, attention at day-hospital,
any kind of invasive procedure (endoscopy, urinary or vascular catheterization, etc.) or
long-term care facility resident.
- Source: CDC definitions for nosocomial infections will be used as a reference; however,
clinical and microbiological criteria as evaluated by the investigators may be used for
interpretation. A source does not need to be microbiologically confirmed if enough
clinical criteria are present.
- Empirical therapy: administered before susceptibility report is available.
- Definitive therapy: administered once the susceptibility report is available. If
empirical therapy was continued, it is not necessary to fill in the definitive therapy
data.
- Outcome definitions:
- Improvement: partial control or resolution of signs and symptoms related to the
infection, or resolution but antibiotic therapy is still necessary.
- Non-improvement or deterioration: clinical situation qualified as similar or worse
in comparison to that at the point of diagnosis of bacteremia.
- Cure: resolution of all signs and symptoms related to the infection, and antibiotic
therapy is no longer necessary.
- Dead: death of the patient for whatever the reason.
- Renal toxicity: development of acute kidney injury according to RIFLE criteria
(Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality
Initiative workgroup: Acute renal failure - definition, outcome measures, animal
models, fluid therapy and information technology needs: The second international
consensus conference of the acute dialysis quality initiative (ADQI) group. Crit
Care 2004, 8:R204 - R212.
- Liver toxicity: Patients will be considered to have hepatotoxicity when they
presented alanine transaminase, aspartate aminotransferase or bilirubin elevations
of more than two times the upper limit of the normal range. Toxicity is considered
severe when symptomatic elevations are more than three times or asymptomatic
elevations are more than five times the normal levels.
- Severe adverse event (SAD): Any event that becomes fatal or life-threatening,
produces a significant or persistent alteration (according to the Principal
Investigator), requires patient hospitalization or prolongation of an existing
hospitalization, produces a congenital anomaly or results in overdose of the drugs
included in this stud. Any toxicity of grade 4 will be considered a SAD (National
Cancer Institute Common Toxicity Criteria Version 3.0).
Quality of data
Data will be approved and signed by the responsible investigator in each center. It is
recommended that data collectors designated by PIs in each Institution are trained in Good
Clinical Practice. All data will be centrally reviewed; queries will be sent for missing data
as well as data showing inconsistencies or discrepancies. Data will be analysed per center;
those centers showing significant differences with the average will be requested to review
their data.
Statistical Analysis Plan
• Objective 1: To evaluate the efficacy and safety of different antibiotics used for the
treatment of infections caused by ESBL- and carbapenemase-producing Enterobacterales in the
SOT population.
Separate statistical analyses will be performed by grouping the different antibiotics to be
evaluated in the two subcohorts of empirical and definitive therapy, which will be analysed
separately; active/inactive empirical therapy will be a potential confounder when analysing
definitive therapy and viceversa. To be assigned to specific treatment arms, patients must
have received the drugs according to the following specific criteria:
- Empirical therapy: patients received the drug in monotherapy (except if combination is
considered) within 24 hours of the blood culture being drawn and prior to availability
of antibiogram results. The antibiotic must have been administered for at least 48
hours, with the single exception of patients who died before 48 hours, who will be
included if death occurred after 1 complete day of therapy with the assigned regimen
(and will be otherwise excluded).
- Definitive therapy: the drug was administered in monotherapy (except if combination is
considered) once susceptibility data was available. When more than one drug was used,
only drugs that were administered for at least half the duration of the definitive
therapy will be included in this study.
The primary endpoint variable, namely "mortality from any cause until day 30", of patients
treated in both cohorts will be plotted using Kaplan-Meier curves and compared using the
log-rank test. Multivariate analyses will be performed using Cox regression. The other
primary endpoint variable, "Cure rate at day 14", will be analysed as a dichotomous outcome.
Regression analyses will use the logistic regression model. Variables with p value <0.2 in
the bivariate analysis will be introduced into models (including those related to
transplant). A propensity score (the probability of receiving each of the two treatment types
under comparison) will be calculated using a non-parsimonious multivariate logistic
regression model in which the treatment type will be the outcome variable and propensity
scores will be introduced into the models. Interactions between treatment and other variables
will be explored and included in the model if they cause a significant modifying effect.
Variables will be selected using a backward stepwise process. Goodness of fit will be
assessed all throughout. The Akaike Information Criterion (AIC) will be used to select the
final logistic models. The models chosen will be those that minimize the Kullback-Leibler
divergence between the model and the actual data. The intraclass correlation coefficient will
be calculated in order to assess the need for controlling the "Center effect" through a
multilevel analysis.
If the sample size is sufficient, an additional analysis restricted to patients matched on
the basis of propensity score, will also be performed. Each patient who received one type of
treatment will be matched with one who received treatment with the other type of antibiotic
evaluated, using calipers of width equal to 0.2 of the standard deviation of the logit of the
propensity score.
• Objective 2. To compare the efficacy of different antimicrobials between SOT and non-SOT
patients (using matched controls from the "non-transplant" INCREMENT cohort).
- Cases that occurred in transplant patients (Transplant-INCREMENT cohort) will be
controlled with cases in non-transplant patients selected from the INCREMENT cohort. Two
control groups will be defined according to the following criteria:
- Clinical variables: age, source of BSI, severity of SIRS (septic shock),
acquisition.
- Propensity score to receive a particular treatment.
- Subcohorts with patients treated with the treatments to be compared will be selected.
- The same criteria about empirical and definitive treatments from objective 1 will be
followed.
- Primary endpoints will also be the same than for objective 1, i.e. "mortality from any
cause until day 30" and "cure rate at day 14".
- A propensity score to receive the two treatment types under comparison will be
calculated by obtaining a non-parsimonious multivariate model by logistic regression in
which the outcome variable will be the treatment type. Explanatory variables will
include age, gender, center, type of ward, acquisition, Charlson index, Pitt score,
severity of SIRS and source.
- After univariate analysis, multivariate analysis to investigate the adjusted association
of treatment type and transplantation with the main and secondary outcome variables will
be performed by using logistic regression (for clinical response at day 14) and by Cox
regression for mortality. If time until death is unavailable, logistic regression will
be used for 30-day mortality. Logistic regression will also be used for 72-hour and
30-day clinical response. The propensity score will be added in all cases; also,
Charlson score, Pitt score, severity of SIRS, source and transplant-related variables
will be added. Interactions between treatment and other variables will be explored and
included in the model if they cause a significant modifying effect. Variables will be
selected using a backward stepwise process. Goodness of fit will be assessed throughout.
The Akaike Information Criterion (AIC) will be used to select the final logistic models.
The models chosen will be those that minimize the Kullback-Leibler divergence between
the model and the actual data. The intraclass correlation coefficient will be calculated
in order to assess the necessity of controlling the "Center effect" through a multilevel
analysis.
The analyses will be performed using R software (version 3.0.1), SPSS 18.0 software and
multilevel analysis (MLwiN Version 2.1, University of Bristol).
Microbiological studies
Feasibility tests provided by the different institutions confirmed that most participating
hospitals have a stock collection of ESBL and/or carbapenemase producers associated with the
clinical cases that will be included in the INCREMENT-SOT database during the study period.
Participating centers will be invited to keep these multiresistant isolates until funding is
available to ship these bacterial samples from the different participating institutions to a
central laboratory in Spain, in order to generate a central collection of microorganisms.
This central collection of multidrug-resistant Enterobacterales will be used to conduct
phenotypic (antimicrobial susceptibility by microdilution) and genotypic studies (resistance
determinants, molecular typing, plasmids study, phylogenetic studies) and the relation of
these parameters with clinical data will be evaluated. Also, once the collection is
generated, it is expected that research groups in the consortium will be in a strong position
to apply for funding in competitive calls to conduct this type of studies.
