Introduction on why researchers should be aware of internal

RESEARCH ARTICLE Open Access

Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram- negative bacteria: relevance to external validity Vered Daitch1,2* , Mical Paul3,4, George L. Daikos5,6, Emanuele Durante-Mangoni7, Dafna Yahav1,8, Yehuda Carmeli1,9,10, Yael Dishon Benattar7,11, Anna Skiada5,6, Roberto Andini7, Noa Eliakim-Raz1,2, Amir Nutman1,10, Oren Zusman1,2ˆ, Anastasia Antoniadou6,12, Giusi Cavezza7, Amos Adler13, Yaakov Dickstein3, Ioannis Pavleas14, Rosa Zampino7, Roni Bitterman3,4, Hiba Zayyad3, Fidi Koppel3, Yael Zak-Doron3, Inbar Levi1,10, Tanya Babich1,2, Adi Turjeman1,2, Haim Ben-Zvi15, Lena E. Friberg16, Johan W. Mouton17ˆ, Ursula Theuretzbacher18 and Leonard Leibovici1,2

Abstract

Background: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study’s population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial.

Methods: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset.

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* Correspondence: [email protected] ˆOren Zusman and Johan W. Mouton are deceased. 1Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Tel Aviv, Israel 2Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Jebotinski 39, Petah Tikva, Israel Full list of author information is available at the end of the article

Daitch et al. BMC Infectious Diseases (2021) 21:309 https://doi.org/10.1186/s12879-021-05995-y

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Results: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/ 701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10–16) vs. 8.5 days (IQR 0–15), p = 0.000]. Univariate analysis showed that non- randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14.

Conclusion: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice.

Trial registration: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.

Keywords: Population external validity, Antimicrobial resistance, Antibiotic treatment

Background Randomized controlled trials (RCTs) are the gold stand- ard for guidelines and evidence-based medicine. Internal validity of an RCT reflects the strengths to support a clinical decision based on study results and the extent to which the results are influenced by bias [1]. Adequate randomization, allocation concealment, blinding, non- selective reporting of outcomes and intention-to-treat analysis, have been identified as important factors in study design to minimize bias in RCTs and increase in- ternal validity [1, 2]. External validity is defined as the extent and manner in which the results of an experi- mental study can be generalized to different subjects and settings. It has two components: population validity, the extent to which the results can be generalized from the specific sample to a defined population, and ecological validity, the extent to which the results can be general- ized from the set of environmental conditions created by the researcher to other environmental conditions/set- tings [3]. The population external validity of RCTs relies firstly

on the inclusion and exclusion criteria. Secondly, it relies on the population of patients actually recruited. Inclu- sion and exclusion criteria should be defined precisely, clearly and unambiguously [2]. Studies have shown that patients recruited into RCTs were sometimes different from those who were eligible but not recruited in terms of age, gender, educational status, socioeconomic status, place of residence, ability to provide informed consent and severity of disease. Patients that could not provide informed consent, and thus were not included, had more severe disease and their outcome was often worse com- pared to patients included in trials [4–6]. The problem of external validity is particularly relevant to registration trials, which typically specify numerous exclusion cri- teria. In order to apply a study’s results, one should be

able to assess its population external validity; however, few studies to date have done so [7–12]. We performed an investigator-initiated, multicenter,

open-label, parallel group, randomized controlled trial (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria (CR GNB). The RCT differed from typical registration trials in its design, particularly in its broad eligibility criteria and in its limited exclusion criteria that were meant to reflect “real life patients”. The design, methods, and results have been previously published [13, 14]. In order to examine the study’s popu- lation external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial that compared the char- acteristics and outcomes of randomized (included) and non-randomized (excluded) AIDA study patients.

Methods Study design and participants We compared patients randomized in the trial (interven- tional arm) to those fulfilling clinical and microbiological inclusion criteria who were not randomized due to ex- clusion from the trial (observational arm). The study was conducted between October 1st, 2013

and January 31st, 2017 (during the RCT recruitment period) in Laikon and Attikon Hospitals in Athens, Greece; Tel Aviv Sourasky Medical Center (Tel Aviv), Rabin Medical Center, Beilinson Hospital (Petah-Tikva) and Rambam Health Care Center (Haifa), Israel; and Monaldi Hospital, Naples, Italy. Study population included adults (18+) with severe in-

fections (requiring hospitalization or hospital acquired), caused by CR GNB that are susceptible to colistin, aminoglycosides, sulbactam, tetracyclines, tigecycline,

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and co-trimoxazole. Infections included bacteraemia, definite ventilator associated or hospital-acquired pneu- monia, probable ventilator-associated pneumonia, and urosepsis. Polymicrobial infections comprising carbapenem-susceptible GNB were excluded from the RCT and from the observational arm. Treatment in the interventional arm included intra-

venous colistin or colistin combined with meropenem. Colistin was administered as a 9-million unit (MIU) loading dose, followed by 4.5-MIU maintenance doses every 12 h, adjusted for renal function in patients with creatinine clearance of less than 50mL/min. Meropenem was given as a 2 g extended-infusion (3 h) every 8 h, ad- justed for renal function. Patients excluded from the RCT for one or more rea-

sons, but otherwise fulfilling clinical and microbiological inclusion criteria were included in the observational arm: refusal to participate; previous colistin treatment for more than 96 h at eligibility assessment; and prior in- clusion in the RCT. Treatment in the observational arm was based on the attending physicians’ decisions.

Outcomes The primary outcome was clinical failure at 14 days after the first positive culture was obtained. The outcome was a composite of: patient deceased, systolic blood pres- sure < 90 mmHg or the need for vasopressor support, no stability or improvement in Sequential Organ Failure As- sessment (SOFA) score, and for patients with bacteremia due to growth of the initial isolate in blood cultures taken on day 14. Secondary outcomes collected for this study were mortality at 14 and 28 days. We also compared demographic data, background

conditions, source of infection, devices present at in- fection onset, infection characteristics, and antibiotic treatment.

Ethics Both RCT and observational study were approved by local ethics committee in each site. Data on excluded pa- tients (observational arm) were collected through elec- tronic records. Informed consent was obtained for all RCT participants (interventional arm). In Israel, the RCT was approved as ‘emergency research’; patients who were not able to provide informed consent and did not have a legal guardian were included by the consent of an approved independent physician (providing direct patient care but not participating in the trial) and a fam- ily member. In Italy and Greece, a relative was an ac- ceptable surrogate for patients that were unable to provide informed consent. In both cases, if the patient has improved, he was asked to provide an informed con- sent for participation. In the case of refusal, the patient was removed from the trial.

Statistical analysis Analyses were performed using the Statistical Package for the Social Sciences 25 (SPSS Inc.). Categorical data were compared using the chi-square test. A Kolmogorov-Smirnov test was carried out in order to determine whether the distributions of continuous variables were normal. Continuous variables were ana- lyzed using t-test or Mann-Whitney-U test as appro- priate. To examine risk factors for clinical failure on day 14 focusing on exclusion from the RCT, we performed a multivariable logistic regression. For the selection of our final model, we used Akaike’s Infor- mation Criterion. Nine models were tested to find the best fit. Different sets of significant variables (p < 0.1) were entered in consideration of clinical relevance. In- teractions between exclusion from the RCT and other variables were not tested due to lack of clinical reasoning.”

Results Analysis was performed on 701 patients, including 295 non-randomized patients in the observational arm and 406 RCT patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for not including suitable

patients in the RCT was refusal to participate [62% (183/ 295)]. 20.7% (62/295) of patients were excluded due to treatment with colistin for more than 96 h, and 16.9% (50/295) were excluded for prior inclusion in the RCT.

Patients’ characteristics Non-randomized and RCT patients were similar in most of the demographic and background parameters. There were more patients with dementia in the RCT [10.7% (49/406) vs. 5.8% (17/295), p = 0.050]. Hematological malignancies were more common in non- randomized patients [8.5% (25/295) vs. 3.4% (14/406), p = 0.004]. At infection onset, RCT patients had more arterial lines [37.2% (151/406) vs. 25.8% (76/295), p = 0.001] central venous catheters [55.4% (225/406) vs. 40.3% (119/295), p = 0.000] and urinary catheters [87.2% (354/406) vs. 77.3% (228/295), p = 0.001] than non-randomized pa- tients (Table 1).

Infection characteristics and antibiotic treatment Severity of infection was similar in the two groups, as ev- idenced by similar SOFA scores, need for hemodynamic support, blood pressure and body temperature. Patients not randomized were less likely to acquire their infection in the intensive care unit [22.7% (67/295) vs. 30.5% (124/ 406). p = 0.022], to be infected with Enterobacteriacaeae [35/295 (11.9%) vs. 73/406 (18%), p = 0.027]; and more likely to have urinary tract infection [32/295 (10.8%) vs. 26/406 (6.4%), p = 0.035]. The minimum inhibitory

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concentration (MIC) of > 0.5 mg/L for colistin was more prevalent in randomized patients [24.3% (85/350) vs. 7.7% (18/233), p = 0.000] [15]. RCT patients received higher rates of colistin-

meropenem combination therapy than non-randomized patients [51.2% (208/406) vs. 31.9% (53/166), p = 0.000]. Colistin loading dose was administered more often to randomized patients [92.6% (376/406) vs. 73.5% (122/ 166), p = 0.000]. No difference was observed in mean co- listin maintenance dose per day between the two groups. Among 14-day survivors, treatment with colistin was

longer in randomized patients than in non-randomized patients [13 days (IQR 10–16) vs. 8.5 days (IQR 0–15), p = 0.000] (Table 2).

Outcomes More non-randomized patients met the criteria for the primary outcome, clinical failure at day 14, than ran- domized patients [82% (242/295) vs. 75.5% (307/406), p = 0.042]. Mortality rates were higher in non- random- ized patients [40.2% (117/295) vs. 33% (134/406 in the RCT patients, p = 0.051]. The difference between the

Table 1 Patients’ characteristics

Excluded from randomized controlled trial (N = 295)

Included in randomized controlled trial (N = 406)

P value

Demographics and background

Age (Mean ± SD), year 65 ± 18 66 ± 17 0.411

Gender (female) 101 (34.2%) 151 (37.2%) 0.421

Country 0.000

Israel 274 (92.9%) 270 (66.5%)

Greece 16 (5.4%) 76 (18.7%)

Italy 5 (1.7%) 60 (14.8%)

Admitted from home 204 (69.2%) 276 (68%) 0.742

BMI, kg/m2 27.1 (6.7) 27.4 (5.8) 0.610

Charlson Score (Mean ± SD) 2 ± 2 2 ± 2 0.497

Dementia 17 (5.8%) 49 (10.7%) 0.050

Diabetes 61 (20.7%) 90 (22.2%) 0.636

Chronic kidney disease 71 (24.1%) 79 (19.5%) 0.129

Hematological Malignancy 25 (8.5%) 14 (3.4%) 0.004

Congestive heart failure 66 (22.4%) 92 (22.7%) 0.928

Chronic pulmonary disease 57 (19.3%) 91 (22.4%) 0.322

Immune suppressive therapy 54 (18.3%) 61 (15%) 0.247

Known colonization by pathogen before infection 69 (23.4%) 96 (23.6%) 0.937

Recent surgery 83 (28.1%) 114 (28.1%) 0.987

Status at infection onset (culture taken time)

Temperature, °C (SD) 37.9 (1.7) 38.0 (1.7) 0.655

Systolic blood pressure, mm Hg (SD) 106 (24) 109 (21) 0.054

Haemodynamic support 68 (24.2%) 75 (18.5%) 0.069

Mechanical ventilation (invasive) 198 (69.5%) 264 (65%) 0.221

Haemodialysis 11 (3.9%) 27 (6.7%) 0.118

SOFA score (Mean ± SD) 6 ± 3 6 ± 3 0.755

Creatinine Clearance (Cockcroft-Gault Equation), mL/min (Percentiles 25–75)

59.79 (32.54–108.58) 69.95 (41.21–126.27) 0.012

Albumin, g/dL (SD) 2.3 (0.6) 2.4 (0.7) 0.285

White blood cells, thousands/mL (SD) 13.22 (9.85) 14.12 (8.89) 0.212

Arterial line 76 (25.8%) 151 (37.2%) 0.001

Central venous catheter 119 (40.3%) 225 (55.4%) 0.000

Urinary catheter 228 (77.3%) 354 (87.2%) 0.001

Nasogastric tube 201 (68.1%) 285 (70.2%) 0.559

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two groups waned at the end of study: 28-day mortality was 47.8% (138/295) in the non- randomized patients vs. 44.3% (180/406) in RCT patients. Univariate analysis for clinical failure at day 14 is dis-

played in Table 3. At multivariable logistic regression, male gender, age,

hemodynamic support, and acquisition of the infection in the intensive care unit were associated with higher rates of 14-day clinical failure. Pseudomonas/other bac- teria as initial isolate were associated with lower rates of 14-day clinical failure. Non-inclusion in the RCT was not an independent risk factor for clinical failure at day 14 (Table 4).

Discussion In our study, patients not randomized in the trial were similar to randomized patients in their baseline charac- teristics, though RCT patients showed minor differences towards a more severe infection. They had more lines and catheters and acquired their infection more often in the intensive care unit. Non- randomized patients were less infected by Enterobacteriaceae, showed lower MIC distributions for colistin, and were presented with higher rates of urinary tract infection.

Univariate analysis showed that non- randomized pa- tients were more inclined to clinical failure on day 14 from infection onset. However, on multivariate analysis exclusion from the RCT was not an independent risk factor for clinical failure. The major reason for exclusion from the RCT was re-

fusal of the patient, the legal guardian, or the treating physician to participate in the trial. In this study, we were authorized by the local ethics committees to recruit patients who were not able to provide informed consent and did not have a legal guardian, with the consent of an approved independent physician or a family member (as described in the Ethics section). This allowed the inclu- sion of severely ill patients that characterize the AIDA trial. On the other hand, patient refusal implied that pa- tients who were able to consent refused randomization, and this translated into the inclusion of less severely ill patients in the observational arm. Non-randomized pa- tients suffered more often from hematological malignan- cies. This could be a result of the patients’ or treating physicians’ concern regarding the inclusion of a patient with a compromised immune system. Creatinine clear- ance levels were lower in non- randomized patients, per- haps reflecting the reluctance to include patients with

Table 2 Infection characteristics and antibiotic treatmenta

Excluded from randomized controlled trial (N = 295)

Included in randomized controlled trial (N = 406)

P value

Infection characteristics

Acquisition of infection in the intensive care unit 67 (22.7%) 124 (30.5%) 0.022

Pathogen

Acinetobacter baumannii 236 (80%) 312 (76.8%) 0.318

Enterobacterales 35 (11.9%) 73 (18%) 0.027

Pseudomonas/other 24 (8.1%) 21 (5.2%) 0.114

Type of infection

Bacteraemia 109 (36.9%) 173 (42.6%) 0.131

Ventilator-associated or hospital-acquired pneumonia 140 (47.5%) 182 (44.8%) 0.490

Probable ventilator-associated pneumonia 14 (4.7%) 25 (6.2%) 0.421

Urinary tract infection 32 (10.8%) 26 (6.4%) 0.035

Colistin MIC distribution > 0.5 mg/L 18 (7.7%), n = 233 85 (24.3%), n = 350 0.000

Antibiotic treatment 0.000

Colistin 113 (68.1%), n = 166 198 (48.8%)

Colistin and meropenem 53 (31.9%), n = 166 208 (51.2%)

Colistin loading dose 122 (73.5%), n = 166 376 (92.6%) 0.000

Treatment days in patients alive ≥14 days, median (Percentiles 25–75)

8.5 (0–15), n = 200 13 (10–16), n = 273 0.000

Mean colistin maintenance dose per day, million units (percentiles 25–75)

Creatinine clearance< 50ml/min 4.2 (2.1–6.0) 4.0 (3.0–6.0) 0.629

Creatinine clearance≥50ml/min 8.6 (5.8–9.0) 8.5 (7.0–9.0) 0.239 aNumbers apply to all patients in the group unless stated otherwise

Daitch et al. BMC Infectious Diseases (2021) 21:309 Page 5 of 9

impaired kidney function into a trial involving a nephro- toxic drug such as colistin. No significant difference between colistin monotherapy

and combination therapy was observed for clinical failure at day 14 in included and excluded patients. Per AIDA RCT protocol, ~ 50% of patients received colistin-meropenem combination therapy. Colistin was administered as a 9-

million-unit (MIU) loading dose followed by mainten- ance doses, with a minimum treatment period of 7 days. Non-randomized patients received mainly colis- tin monotherapy, reflecting the standard of care, with a lower rate of colistin loading dose administration and a shorter treatment period. The difference in management and the significantly related variates

Table 3 Univariate analysis for clinical failure at day 14a

Clinical success at day 14 (N = 152)

Clinical failure at day 14 (N = 549)

P value

Age (Mean ± SD), year 62.79 (18.514) 66.08 (16.975) 0.038

Gender (female) 68 (44.7%) 184 (33.5%) 0.011

Country 0.001

Israel 113 (74.3%) 431 (78.5%)

Greece 32 (21.1%) 60 (10.9%)

Italy 7 (4.6%) 58 (10.6%)

Hematological malignancy 2 (1.3%) 37 (6.7%) 0.010

Congenative heart failure 25 (16.4%) 133 (24.2%) 0.042

Arterial line 35 (23%) 192 (35%) 0.005

Chronic pulmonary disease 23 (15.1%) 125 (22.8%) 0.041

Systolic blood pressure, mm Hg (SD) 111.97 (20.539) 106.66 (22.499) 0.009

Haemodynamic support 16 (10.6%) 127 (23.7%) 0.000

Mechanical ventilation (invasive) 81 (53.6%) 381 (70.6%) 0.000

Haemodialysis 1 (0.7%) 37 (6.9%) 0.003

Creatinine clearance (Cockcroft-Gault Equation), mL/min (Percentiles 25–75)

72.60 (41.16–132.14) 64.01 (36.08–118.69) 0.199

Albumin, g/dL (SD) 2.46 (0.678) 2.327 (0.6383) 0.035

Nasogastric tube 92 (60.5%) 394 (71.8%) 0.008

Pathogen

Acinetobacter baumannii 100 (65.8%) 448 (81.6%) 0.000

Enterobacteriacaeae 35 (23%) 73 (13.3%) 0.003

Pseudomonas/other 17 (11.1%) 28 (5.1%) 0.007

Type of infection

Bacteraemia 68 (44.7%) 214 (39%) 0.200

Ventilator-associated or hospital-acquired pneumonia 55 (36.2%) 267 (48.6%) 0.006

Probable ventilator-associated pneumonia 10 (6.6%) 29 (5.3%) 0.537

Urinary tract infection 19 (12.5%) 39 (7.1%) 0.033

Acquisition of infection in the intensive care unit 24 (15.6%) 167 (30.4%) 0.000

Exclusion from the RCT 53 (34.9%) 242 (44.1%) 0.042

Colistin MIC distribution > 0.5 mg/L 27 (21.3%), n = 127 76 (16.7%), n = 456 0.230

Antibiotic treatment

Combination arm: colistin and meropenem 68 (50.7%), n = 134 193 (44.1%), n = 438 0.174

No loading dose 12 (9.0%), n = 134 62 (14.2%), n = 438 0.117

Treatment days in patients alive ≥14 days, median (Percentiles 25–75)

13 (8–16) 8 (4–14) 0.000

Mean colistin maintenance dose per day, million units (Percentiles 25–75)

7.9 (5.0–9.0) 7.2 (4.0–9.0) 0.330

aNumbers apply to all patients in the group unless stated otherwise

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described in the logistic regression can explain the higher rates of clinical failure in non- randomized patients. In a trial published in 2015, Paul et al. examined the

external validity of a RCT comparing trimethoprim- sulfamethoxazole versus vancomycin for the treatment of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections. The major point of difference from AIDA study was that patients that were not able to sign an informed consent and did not have a legal guardian could not enter the MRSA RCT- thus excluded patients were more ill than included patients, and the differences between the two populations were more substantial, in- cluding primary outcomes, with excluded patients show- ing significantly higher clinical failure and 30-day all- cause mortality rates [5]. In order to minimize differences between the study

sample and “real-world” patients, the AIDA RCT did not exclude patients for underlying conditions or sepsis se- verity while taking into account the potential comprom- ise of internal validity caused by increasing heterogeneity of the recruited patients. This is of major importance, especially in comparison with registration or pharma- ceutical company-sponsored trials. Ha et al. examined the proportion of patients encountered during routine clinical practice who would qualify for enrollment into a pivotal RCT of biological agents for inflammatory bowel disease (IBD). In this retrospective cohort study, the eli- gible patients were examined for inclusion in at least one of seven selected published RCTs. Only ~ 30% of patients would have qualified for enrollment due to nu- merous exclusion criteria [16]. A literature review pub- lished in 2015 identified the use of restrictive inclusion/ exclusion criteria as one of the key factors that limited external validity of trial findings [17]. This issue raises the importance of designing an RCT to include a diverse population with limited exclusion criteria so that the re- sults can be generalized to the population in hand.

Our study has few limitations. First, the observa- tional cohort included patients excluded due to three out of seven exclusion criteria which account for most of the observational sample [81.7% (295/361)], thus not all RCT excluded patients entered the obser- vational arm. We chose to focus on these exclusion criteria since they truly reflect patients compatible for recruitment. Second, this study focuses on one aspect of external validity- comparison of characteristics and outcomes of excluded and included patients. This as- pect refers to the population validity component and addresses the question of whether the findings of a study can be generalized to patients with characteris- tics that are different from those in the study, or pa- tients who are treated or followed up differently. For a broader evaluation of external validity, it will be in- teresting to test ecological validity which specifically examines whether the findings of a study can be gen- eralized to different clinical settings in everyday life.

Conclusions The similarity between patients in the observational and RCT arms has strengthened our confidence in the popu- lation external validity of the AIDA trial. Limited exclu- sion criteria and access to recruiting the most severely ill patients into the trial population are key elements con- ferring the high population external validity in the AIDA trial, and overall for this ty

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