Background and Rationale
Advanced Risk Stratification of Pulmonary Embolism
Assessment of the clinical severity of acute pulmonary embolism (PE) is based on the estimated risk of early (in-hospital or 30-day) mortality. High-risk PE, defined by the presence of hemodynamic instability at presentation, is a life-threatening condition in which prompt reperfusion treatment is needed to increase the chances of survival.[1 ] However, the vast majority of patients with acute PE do not present with overt hemodynamic compromise.[2 ]
[3 ] Within this large, apparently stable group, prediction scores derived from clinical variables permit further risk stratification. For example, a Pulmonary Embolism Severity Index (PESI) risk class of I or II, a simplified PESI (sPESI) of 0, or the absence of Hestia criteria all have a high negative predictive value for ruling out an early adverse outcome (low-risk PE).[4 ]
[5 ]
[6 ] On the other hand, hemodynamically stable patients who do not fulfill these criteria belong to the intermediate-risk category. Numerous studies could show that, in intermediate-risk PE, imaging parameters and laboratory biomarkers possess additive prognostic value, complementing each other[7 ]
[8 ] as well as baseline clinical parameters.[9 ]
[10 ] Accordingly, patients are classified into the intermediate–high-risk category if they have evidence of right ventricular (RV) dysfunction on echocardiography or computed tomography pulmonary angiography, in combination with elevated plasma cardiac troponin levels.[1 ]
Unfavorable Risk-to-benefit Profile of Full-Dose Systemic Thrombolysis
The superior hemodynamic effects and faster onset of action (compared with heparin anticoagulation alone) of systemic thrombolytic (fibrinolytic) treatment have been established, and its use is recommended in the emergency setting of acute high-risk PE.[11 ] However, it has remained controversial for decades whether systemic thrombolysis might also improve the clinical outcome of hemodynamically stable patients,[12 ] particularly those with intermediate–high-risk PE. Following first promising data in the early 2000s,[13 ] the Pulmonary Embolism International THrOmbolysis (PEITHO) trial confirmed the clinical efficacy of full-dose thrombolysis (using tenecteplase) in this risk group.[14 ] That study showed a significant reduction (odds ratio [OR]: 0.44; 95% confidence interval [CI]: 0.23–0.87) in the clinical composite of death from any cause or hemodynamic collapse within 7 days after randomization. However, this benefit came at a high price: in PEITHO, stroke occurred in 12 patients (2.4%) randomized to the thrombolysis arm (OR: 12.10; 95% CI: 1.57–93.39 vs. heparin alone), being hemorrhagic in 10 cases.[14 ] Considering the high risk of intracranial or other life-threatening bleeding events, which was subsequently confirmed by meta-analyses,[15 ] current guidelines do not recommend systemic thrombolysis as first-line treatment in intermediate–high-risk PE.[1 ]
[16 ] Lastly, the PEITHO trial had not been designed to answer the question whether early systemic thrombolysis may prevent the development of late sequelae thromboembolic pulmonary hypertension (chronic thromboembolic pulmonary hypertension) after intermediate-risk PE.[17 ]
Reduced-Dose Thrombolysis Might Improve Safety While Maintaining Efficacy
In patients with acute PE, three small randomized trials compared a reduced dose of alteplase with the conventional 100 mg regimen (received by a total of 162 and 99 patients, respectively, in the pooled study population).[18 ]
[19 ]
[20 ] The reduced-dosage regimens varied amongst the studies: in one of them, 50 mg of alteplase was infused over 2 hours,[20 ] whereas in the two other studies, a weight-adapted dose of 0.6 mg/kg, up to a total of 50 mg, was given over 15 minutes.[18 ]
[19 ] There were no significant differences in efficacy between the reduced-dose and the standard-dose regimen, as judged by changes in pulmonary artery pressure, cardiac index or residual vascular obstruction at 24 hours, or the incidence of PE recurrence.[18 ]
[19 ]
[20 ] In addition, and importantly, a meta-analysis suggested that a reduced dosage may be associated with reduction in the risk of major bleeding (OR: 0.33; 95% CI: 0.12–0.91).[21 ]
The efficacy of the reduced-dose regimen is further supported by two studies comparing alteplase, at the dose of 0.6 mg/kg[22 ] or 0.5 mg/kg (maximum of 50 mg),[23 ] with heparin alone in patients with acute PE. A greater improvement of vascular obstruction was observed with alteplase in the former study,[22 ] whereas the latter reported a reduction in the combined endpoint of persistent pulmonary hypertension or recurrent PE over the long term.[23 ]
Taken together, reperfusion treatment employing systemic thrombolysis exerts favorable hemodynamic effects, and thrombolytic regimens may be capable of improving the prognosis of patients with acute intermediate–high-risk PE. Nevertheless, the bleeding risk of full-dose intravenous thrombolysis is too high to justify its use as first-line therapy in this risk category. Today, reduced-dose regimens are becoming increasingly popular in clinical practice worldwide, despite the explicit warning by scientific societies and guidelines that the available evidence is not (yet) sufficient to support their efficacy and safety. This potentially dangerous gap in knowledge must therefore be closed as soon as possible. An adequately powered randomized placebo-controlled clinical trial, focusing on clinically relevant efficacy and safety outcomes, is the only way to determine the benefits versus risks of reduced-dose thrombolysis in acute PE.
Study Overview
Study Design and Objectives
The Pulmonary Embolism International Trial (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. The primary objective is to assess the efficacy (defined as the ability to prevent death, hemodynamic decompensation, or PE recurrence) of reduced-dose intravenous thrombolytic therapy with alteplase, against the background of standard care (heparin anticoagulation), in patients with acute intermediate–high-risk PE, 30 days after randomization. The secondary objectives are to assess (1) the safety, net clinical benefit, and impact of reduced-dose thrombolytic therapy on overall mortality in patients with intermediate–high-risk PE, as well as (2) the effect on long-term mortality, functional impairment, residual RV dysfunction, and the incidence of chronic thromboembolic pulmonary hypertension.
Patient Population and Eligibility
The key inclusion and exclusion criteria are summarized in [Table 1 ]. In this context, it is important to explain the rationale for the advanced definition of intermediate–high-risk PE used in the present study. In fact, both past[24 ] and current[1 ] guidelines defined intermediate–high-risk PE based “exclusively” on imaging (evidence of RV dysfunction) and biochemical (circulating levels of elevated laboratory biomarkers) criteria. Although these modalities generally possess high sensitivity, validated in several cohort studies and a randomized trial (reviewed in Konstantinides et al[24 ]), their prognostic specificity as standalone tools may be too low to predict threatening cardiorespiratory decompensation.[13 ]
[14 ] They may thus not suffice to identify the patients closer to the “upper border” of the intermediate-risk zone, who are expected to obtain the largest possible clinical benefit from early thrombolytic treatment. To address this limitation, we sought to identify additional baseline predictors of early life-threatening events in the population of the large PEITHO trial, in which overall early mortality was low.[14 ] We found that initial systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min (or, as a surrogate, an arterial oxygen saturation <90% on room air) at presentation, or a history of chronic heart failure, predicted, alone or in combination, death from any cause, hemodynamic decompensation, or objectively confirmed recurrent PE within 30 days of randomization. The presence of at least one of these criteria thus defined an enriched patient population (53% of the patients enrolled in that study), in which the incidence of the composite clinical outcome was 11.2% in the control group as opposed to as low as 3.7% in the thrombolysis group.[25 ] This group was defined as the target population in the present trial, with the aim to obtain an optimized benefit-to-risk ratio from early thrombolysis.
Table 1
Key inclusion and exclusion criteria
Inclusion criteria
Exclusion criteria
1. Age 18 years or older
2. Objectively confirmed acute PE with first symptoms ≤2 weeks before randomization, ≥1 of the following criteria required:
a. ≥1 segmental ventilation-perfusion mismatch on lung scan
b. CTPA/pulmonary angiography showing filling defect or abrupt obstruction of a segmental/more proximal pulmonary artery
3. Elevated risk of early death or hemodynamic collapse, indicated by ≥1 of the following criteria:
a. SBP ≤ 110 mm Hg over ≥15 minutes
b. Temporary need for fluid resuscitation and/or treatment with low-dose catecholamines because of arterial hypotension at presentation, provided that the patient could be stabilized within 2 hours of admission and maintains SBP of ≥90 mm Hg and adequate organ perfusion without catecholamine infusion
c. Respiratory rate > 20 per minute or oxygen saturation on pulse oximetry (SpO2 ) < 90% or partial arterial oxygen pressure < 60 mm Hg at rest while breathing room air
d. History of chronic heart failure, defined as previous diagnosis of heart failure with reduced, moderately reduced, or preserved ejection fraction, or treatment for heart failure at any time during the past 12 months
4. RV dysfunction, indicated by RV/LV diameter ratio > 1.0 on echocardiography (apical four-chamber or subcostal four-chamber view) or on CTPA (transverse plane)
5. Serum troponin I or T concentration above the upper limit of local normal using a high-sensitive assay
6. Signed informed consent
Note : Patients who test positive for SARS-CoV-2 may be randomized, if the investigator judges that the acute PE (and not the infection with SARS-CoV-2) is responsible for the patient's clinical, imaging, and hemodynamic parameters meeting the trial's inclusion criteria.
1. High-risk PE with hemodynamic instability[1 ]
2. Active bleeding
3. History of nontraumatic intracranial bleeding
4. Acute ischemic stroke or transient ischemic attack in the past 6 months
5. Neurosurgery or eye surgery; abdominal, cardiac, thoracic, or vascular surgery; or orthopaedic surgery or trauma, in the past 3 weeks
6. Known central nervous system neoplasm or metastasis
7. Platelet count < 100 × 109 /L
8. INR > 1.4
9. Administration of thrombolytic agents in the preceding 4 days
10. Antiplatelet agents other than ASA ≤100 mg once daily; clopidogrel 75 mg once daily or a single loading dose of ASA or clopidogrel
11. Any direct oral anticoagulant within 12 hours of randomization
12. Known significant bleeding risk according to investigator's judgment
13. Vena cava filter insertion in the preceding 4 days
14. Current participation in another clinical trial
15. Previous enrolment in this study
16. Known hypersensitivity to alteplase, gentamicin, any of the excipients of the trial drug, or low-molecular weight heparin
17. Known severe hepatic disease, portal hypertension (with esophageal varices), or active hepatitis
18. Peptic ulcer diagnosed in the past 3 months
19. Pregnancy or parturition within the previous 30 days, or current breastfeeding
20. Women of childbearing potential who do not have a negative pregnancy test and do not use an effective method of birth control
21. Any other condition that the investigator feels would place the patient at increased risk upon start of the investigational treatment
22. Life expectancy <6 months or inability to participate at 6-month follow-up visit
Abbreviations: ASA, acetylsalicylic acid; CTPA, computed tomography pulmonary angiography; INR, international normalized ratio; LV, left ventricular; PE, pulmonary embolism; RV, right ventricular; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SBP, systolic blood pressure.
Treatment Regimens
The diagram shown in [Fig. 1 ] depicts the study flow and the allowed time intervals between consecutive trial procedures and visits. An overview of the tests to be performed and parameters to be collected upon enrolment and at the follow-up visits is provided in [Table 2 ]. Patients fulfilling all the inclusion criteria and none of the exclusion criteria ([Table 1 ]) will be randomized into the experimental or the reference treatment arm. Patients will receive alteplase (if randomized into the experimental arm) or placebo (if randomized into the reference arm), to be given within 30 minutes of randomization as a 15-minute intravenous infusion; the dosage will be 0.6 mg/kg, with the total dose not exceeding 50 mg. If the experimental treatment cannot be given within 30 minutes of randomization, the patient will be analyzed according to the intention-to-treat (ITT) principle.
Fig. 1 Overview of design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial. AEs, adverse events; PE, pulmonary embolism, RV, right ventricular; i.v., intravenously; V, visit.
Table 2
Trial visit plan and data collection schedule
Day (D)0 Inclusion visit
D30 ± 3 days after randomization
Month (M)6 ± 15 days after randomization
M24 ± 30 days after randomization/end of study
In hospital
Outpatient follow-up
Verification of inclusion and exclusion criteria
X
Signed informed consent
X
Randomization
X
Medical interview
- Demographics
- Medical history
- Concomitant antiplatelet and anticoagulant treatment
X
Clinical examination[a ]
X
X
X
X
Troponin I and/or t -test
X
Further laboratory tests[b ]
X
RV/LV diastolic diameter ratio
X
sPESI
X
Study drug administration
X
Echocardiography
X
X
X
Pregnancy test (for women of childbearing age)
X
Documentation of (serious) adverse events[c ]
X
X
Utilization of health care resources
X
X
Abbreviations: LV, left ventricular; RV, right ventricular; sPESI, simplified Pulmonary Embolism Severity Index.
a Including body weight, blood pressure, heart rate, arterial oxygen saturation, respiratory rate, clinical signs of right heart failure.
b Creatinine, international normalized ratio, hemoglobin (1 day after randomization), platelet count (before and after randomization).
c Patients will be continuously monitored for early detection of hemodynamic instability or major bleeding.
Both treatment arms will receive anticoagulant treatment using low-molecular-weight heparin (LMWH) or any other type of heparin approved for the treatment of acute PE, according to local practice. If anticoagulation has been initiated using unfractionated heparin (UFH) and a switch to LMWH is envisaged after randomization, the UFH infusion will be stopped at the time of randomization and the first LMWH subcutaneous injection will be given within 3 hours of the end of UFH infusion. If anticoagulation has been initiated with LMWH as a twice-daily regimen, the next LMWH injection will be given 12 hours after the previous one. If fondaparinux, or LMWH as once-daily injection, has been given before randomization, the next injection will be given 24 hours after the previous one. Due to the longer half-life of fondaparinux as compared with LMWH, a switch from that drug to LMWH (or UFH) is generally recommended over the first 48 hours. The use of direct oral anticoagulants (apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban) and vitamin K antagonists will not be allowed within the first 48 hours after randomization. All approved anticoagulant regimens will be allowed 48 hours after randomization.
As recommended by current guidelines,[1 ] all patients will receive therapeutic anticoagulation for at least 3 months. After the first 3 months, discontinuation or extension of the anticoagulant treatment will be at the discretion of the treating physician.
Outcomes
The efficacy and safety outcomes of the PEITHO-3 trial are summarized in [Table 3 ]. The primary efficacy outcome is the clinical composite of death from any cause, hemodynamic decompensation, or objectively confirmed recurrent PE within 30 days of randomization. When defining the primary efficacy outcome, we took into account that early mortality is relatively low in patients with intermediate-risk PE receiving contemporary, state-of-the-art supportive care such as that provided in the setting of a randomized controlled trial.[14 ] Thus, the sample size required for a trial aiming to show a “pure mortality benefit” from thrombolysis would be prohibitively large. On the other hand, other relevant adverse outcomes, notably early hemodynamic collapse or decompensation, are more frequent in patients with intermediate–high-risk PE treated with anticoagulation, and they represent a valid component of overall clinical efficacy.[14 ] In addition, by including all-cause (and not only PE-related) mortality in the composite primary outcome, we aim to ensure that, if superiority of reduced-dose thrombolysis over heparin alone is shown in the present study, it will have accounted for any thrombolysis-related fatal bleeding events. In the same context, the GUSTO definition of bleeding was chosen because it directly reflects the possible impact of bleeding complications on death or hemodynamic compromise/decompensation. Consequently, possible opposing effects of reduced-dose thrombolysis on efficacy and safety (such as prevention of PE-related death or decompensation at the cost of excessive fatal bleeding or hemorrhage-induced hemodynamic compromise) will both be taken into account in the primary clinical outcome. PEITHO-3 thus aims to provide a clear message to physicians regarding the overall clinical benefit of thrombolysis in patients with intermediate–high-risk PE rigorously defined by clinical, imaging, and biochemical criteria.[25 ]
Table 3
Primary and secondary outcomes
Primary outcome
Clinical composite of death from any cause or hemodynamic decompensation or objectively confirmed recurrent PE within 30 days of randomization
Secondary outcomes
To be included in a hierarchical analysis:
1. Fatal or GUSTO severe or life-threatening bleeding, defined as either intracranial bleeding or bleeding leading to significant hemodynamic compromise requiring treatment,[38 ] within 30 days
2. Net clinical benefit, defined as the composite of the primary efficacy outcome and GUSTO severe or life-threatening bleeding, within 30 days
3. All-cause mortality within 30 days
Not to be included in the hierarchical analysis:
4. PE-related death within 30 days of randomization
5. Hemodynamic decompensation within 30 days
6. Recurrent PE within 30 days
7. Need for rescue thrombolysis, catheter-directed treatment, or surgical embolectomy within 30 days
8. Ischemic or hemorrhagic stroke within 30 days
9. Serious adverse events within 30 days
10. Utilization of health care resources within 30 days and 6 months
11. All-cause mortality at 2 years
12. Persisting dyspnea assessed by the Medical Research Council (MRC) scale at 6 months and at 2 years
13. Functional outcome, using the post-VTE functional scale,[39 ] at 6 months and at 2 years
14. Persistent RV dysfunction, defined as an intermediate or high probability of pulmonary hypertension on echocardiography according to ESC criteria,[40 ] at 6 months and 2 years
15. Confirmed chronic thromboembolic pulmonary hypertension according to ESC criteria[40 ] at 2 years
Abbreviations: ESC, European Society of Cardiology; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; PE, pulmonary embolism; RV, right ventricular; VTE, venous thromboembolism.
All primary and secondary outcomes will be adjudicated by an independent clinical events committee.
Sample Size Calculation and Statistical Analysis Plan
To calculate the sample size for the present study, we performed a post hoc analysis of the population of the PEITHO trial, the largest (full-dose) thrombolysis trial with clinical outcomes conducted to this date.[25 ] This analysis helped to estimate the incidence of the primary efficacy outcome (death from any cause or hemodynamic collapse or objectively confirmed recurrent PE within 30 days of randomization) as defined in the present study, PEITHO-3. More specifically, in the subgroup of patients included in PEITHO, who would have fulfilled the “enriched” inclusion criteria of the present study, the rates were 11.2 and 3.7% in the control and (standard-dose) thrombolysis groups, respectively (relative risk reduction 67%). For estimating efficacy in PEITHO-3, we conservatively assumed a 55% relative risk reduction, corresponding to a 5.0% expected incidence in the reduced-dose thrombolysis group. Taking into account a planned interim analysis (see below) with the Lan and DeMets methods, we calculated that several (n = 305) patients per treatment arm will allow a 80% power to show the expected relative risk reduction. The nominal α at final analysis will be set at 0.049 for the primary analysis according to the Lan–DeMets[26 ] monitoring boundary with an O'Brien–Fleming stopping rule, provided that no sample size modification will be needed; otherwise, the final significance level will be adjusted accordingly.[27 ] Accounting for possible early dropouts, it is planned to enroll and randomize a total of 650 patients; the final size of the trial population will depend on the results of the interim analysis as explained below.
The primary analysis on the primary outcome will be performed in the ITT population applying a logistic regression analysis to account for stratification factors[28 ]
[29 ]; the group variables age (>75 vs. ≤75 years) and country will be included in the model. Results will be presented as OR and associated 95% CI. In addition, two exploratory subgroup analyses will be performed for the primary outcome in the ITT population, according to the following variables: (1) >75 versus ≤75 years, and (2) presence of ≥2 clinical criteria of PE severity at presentation (among the following inclusion criteria: systolic blood pressure ≤ 110 mm Hg; respiratory rate > 20/min or, as a surrogate, arterial oxygen saturation < 90% on room air; history of chronic heart failure) versus one criterion. An interaction term between subgroup variable and the treatment variable will be included in the logistic model, to assess whether the interaction is significantly associated to the primary outcome. Results will be presented as a forest plot.
In addition to improving early clinical outcomes, utilization of health care resources will be recorded for each patient at two time points (30 days and 180 days) postrandomization. For outpatient visits and periods of hospitalization, country-specific standardized unit costs will be applied, representing costs from a societal perspective. In addition, PE-related resource utilization will be recorded.
Safety Monitoring, Interim Analysis, and Stopping Rules
An independent data and safety monitoring board (DSMB) will be assessing the safety of the study. The DSMB will periodically review the serious adverse events (SAEs) with a special attention to the major bleeding events and will communicate its recommendations to the sponsor about stopping or continuing the trial. As specified in a dedicated charter, the frequency of DSMB meetings will be scheduled every 20 SAEs. Additional meetings may be arranged, especially if the SAE numbers are higher than anticipated. An independent statistician will conduct a formal efficacy interim analysis and sample size re-estimation based on the adjudicated primary efficacy outcome of 50% of the expected total number of patients. The superiority of the experimental treatment versus the control arm will be assessed by the chi-square test. To provide an overall two-sided significance level close to 0.05 for the study, the interim analysis will have a Lan–DeMets monitoring boundary with an O'Brien–Fleming stopping rule.[26 ] The study will stop for efficacy if the p -value provided by the chi-square test is ˂0.003. The study will stop for futility if the conditional probability (based on the observed treatment effect) of rejecting the null hypothesis is ˂0.5.
Implications of PEITHO-3
It has been almost 18 years since the first PEITHO trial was launched. The PEITHO investigators set out to resolve a long-lasting controversy concerning the efficacy versus safety of reperfusion treatment for patients with acute PE presenting with findings of acute RV pressure overload and dysfunction despite apparently normal systemic blood pressures.[30 ]
[31 ] PEITHO helped to advance the definition of intermediate-risk PE, and it showed that patients belonging to the intermediate–high-risk class may clinically benefit from systemic thrombolysis as first-line treatment. However, that trial also showed that the bleeding risks of full-dose intravenous thrombolysis predominate over its clinical and hemodynamic effects.[14 ] In view of these results, the focus of the debate has shifted toward identifying safer reperfusion modalities. Percutaneous catheter-directed treatment of acute PE, aiming a mechanical thrombus removal with or without local thrombolysis, has shown promising effects on surrogate imaging or hemodynamic parameters.[32 ]
[33 ]
[34 ]
[35 ] However, for the majority of countries and hospitals around the world, intravenous thrombolysis is expected to remain a more affordable and more feasible option in terms of required expertise, infrastructure, and resources. The present randomized controlled trial will address a large unmet need by testing the hypothesis that reduced-dose systemic thrombolysis may improve the prognosis of patients with acute intermediate–high-risk PE at an acceptably low risk of major bleeding complications. In this context it is further anticipated, as also suggested by the results of meta-analyses,[15 ]
[36 ] that the use of alteplase in the present trial will be associated with a lower risk of intracranial hemorrhage and other major bleeding compared with tenecteplase used in PEITHO.[14 ] If the hypothesis of PEITHO-3 is confirmed, international clinical practice guidelines will most likely revisit their recommendations by including reperfusion and particularly reduced-dose systemic thrombolysis as first-line treatment in this risk class. If the hypothesis is rejected, catheter-directed treatment may become the only option for improving the prognosis of patients with intermediate–high-risk PE,[37 ] provided that it can demonstrate clinical efficacy and safety in future state-of-the-art randomized controlled trials. In any case, the results of the present trial are expected to have a major impact on future risk-adjusted treatment strategies for patients with acute PE.
Study Committees and Investigators
Scientific Steering Committee
Olivier Sanchez, Paris, France; Stavros Konstantinides, Mainz, Germany; Walter Ageno, Varese, Italy; Melanie Ferreira, Almada, Portugal; Menno V. Huisman, Leiden, The Netherlands; David Jiménez, Madrid, Spain; Sandrine Katsahian, Paris, France; Matija Kozak, Ljubljana, Slovenia; Mareike Lankeit, Berlin, Germany; Nicolas Meneveau, Besançon, France; Piotr Pruszczyk, Warsaw, Poland; Antoniu Petris, Iasi, Romania; Marc Righini, Geneva, Switzerland; Branislav Stefanovic, Serbia; Peter Verhamme, Leuven, Belgium; Kerstin de Wit, Hamilton, Ontario, Canada; Andreas Zirlik, Graz, Austria.
Executive Committee
Olivier Sanchez, Paris, France; Stavros Konstantinides, Mainz, Germany; Yvann Frigout, Paris, France; Aurélie Guimfack, Paris, France; Dorothea Becker, Mainz, Germany; Nadine Martin, Mainz, Germany; Louise Goedhart (Aixial, Boulogne-Billancourt, France; contract research organization).
Trial Statisticians
Anaïs Charles-Nelson, Sandrine Katsahian, Eric Vicaut, Paris, France; Harald Binder, Freiburg, Germany.
Data Safety Monitoring Board
Jean-Philippe Collet, Paris, France; Drahomir Aujesky, Bern, Switzerland; Silvy Laporte, Saint Etienne, France.
Clinical Events Adjudication Committee
Joseph Emmerich, Paris, France; Cécile Tromeur, Brest, France; Stefano Barco, Zurich, Switzerland.
