Administrative information
Title {1} | Impact of model-informed precision dosing in adults receiving vancomycin via continuous infusion: a randomized, controlled clinical trial. |
Trial registration {2a and 2b}. | EudraCT number: 2021-003670-31. ClinicalTrials.gov Identifier: NCT05535075. |
Protocol version {3} | Protocol version 3. Protocol date: April 21, 2023. |
Funding {4} | Vancomycin treatment is part of routine care. The MIPD software is provided in kind by the company Insight RX for conducting the trial. |
Author details {5a} | Glenn Van Wynsberge1, Veerle Grootaert2, Franky Buyle1, Jens Van Praet3, Roos Colman4, Ine Moors5, Annemie Somers1,6, Diana Huis in ’t Veld7, Pieter De Cock1,8
1 Department of Pharmacy, Ghent University Hospital, Belgium
2 Department of Pharmacy, General Hospital Sint-Jan Bruges, Belgium
3 Department of Nephrology and Infectious Diseases, General Hospital Sint-Jan Bruges, Belgium
4 Biostatistics Unit, Faculty of Medicine and Health Sciences, Ghent University, Belgium
5 Department of Hematology, Ghent University Hospital, Belgium
6 Faculty of Pharmaceutical Sciences, Ghent University, Belgium
7 Department of General Internal Medicine and Infectious Diseases, Ghent University Hospital, Belgium
8 Department of Basic and Applied Medical Sciences, Ghent University Hospital, Belgium
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Name and contact information for the trial sponsor {5b} | Ghent University Hospital, Ghent, Belgium Contact: Pieter De Cock. Tel: +3293322969 Email: pieter.decock@uzgent.be. |
Role of sponsor {5c} | Responsibilities of the sponsor are: • Central data collection and verification of reportable events. • Notifying investigators and reporting of SUSARs within required timelines. • Preparing standard tables and other relevant information for the Development Safety Update Report (DSUR) in collaboration with the Chief Investigator (CI) and ensuring timely submission to the regular authorities and EC. • Submission of the annual progress reports, including safety summary and deviations. |
Introduction
Background and rationale {6a}
Objectives {7}
Primary objectives
Secondary objectives
Tertiary objectives
Trial design {8}
Methods: participants, interventions, and outcomes
Study setting {9}
Eligibility criteria {10}
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They are admitted to a participating ward unit (hematology, orthopedic, gastrointestinal surgery or internal medicine);
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They have a suspected or confirmed Gram-positive infection;
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Intravenous continuous infusion vancomycin treatment has started or is planned to be started;
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They or their legal representative signed the informed consent form (ICF);
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They were not previously enrolled in this trial.
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Their serum creatinine level at inclusion is above 2.5 mg/dL;
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They are undergoing extracorporeal treatment at inclusion (e.g., extracorporeal membrane oxygenation, dialysis, body cooling);
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The patient’s death is deemed imminent and inevitable.
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Criteria for discontinuing or modifying allocated interventions {11b}
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The patient is requiring extracorporeal treatment (dialysis, extracorporeal membrane oxygenation, body cooling);
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The patient develops acute kidney injury Kidney Disease Improving Global Outcomes (KDIGO) class 3;
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The treating physician’s decision due to other safety reasons than kidney injury;
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The patient is transferred to a ward unit in a hospital not participating in the study;
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The patients’ withdrawal of informed consent.
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary endpoint
Secondary endpoints
Baseline serum creatinine is defined as the most recent documented serum creatinine value within 7 days before the start of the vancomycin therapy. If no value is available, baseline serum creatinine is estimated using the Modification of Diet in Renal Disease (MDRD) study equation assuming that the baseline estimated glomerular filtration rate (eGFR) is 75 ml/min/1.73 m2, in patients with no evidence of chronic kidney disease [16].
AKI is defined as any of the following (not graded): - Increase in SCr by ≥ 0.3 mg/dl within 48 h - Increase in SCr to ≥ 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days |
Stage | Serum creatinine |
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1 | 1.5–1.9 times baseline OR ≥ 0.3 mg/dl increase |
2 | 2.0–2.9 times baseline |
3 | 3.0 times baseline OR Increase in serum creatinine to ≥ 4.0 mg/dl OR Initiation of renal replacement therapy |
Tertiary endpoints
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Interventional arm: AUC24h/MIC of 400–600 mg × h/L assuming a MIC of 1 mg/L;
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Comparator arm: target concentration range for continuous dosing regimens according to institutional guidelines.
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Interventional arm: AUC24h/MIC of 400–600 mg × h/L.
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Comparator arm: target concentration range for continuous dosing regimens according to institutional guidelines.
Participant timeline {13}
Sample size {14}
Recruitment {15}
Patient identification
Patient screening
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Vancomycin treatment
Blood sampling for vancomycin concentration measurement
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Blood sample is drawn approximately 24 h after the start of the loading dose;
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If a sub- or supratherapeutic concentration is measured, the dosing regimen is changed and a repeat sample is taken approximately 24 h after the change of dosing regimen;
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Whenever therapeutic concentrations are reached, a repeat sample is drawn every 3 to 4 days, or sooner (e.g., in case of changing renal function, suspected therapy failure, or major surgery);
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More frequent sampling to ensure efficacious treatment, to avoid toxicity or to rule out sampling errors, is performed at the discretion of the attending physician;
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More delayed or earlier sampling for practical sampling occurs at per standard-of-care and is at the discretion of the attending physician.
Weight
Serum creatinine
Concomitantly administered nephrotoxic comedication
Concomitant antibiotic use
C-reactive protein
Microbiological data
Automated or semi-automated post hoc assessments
AUC estimation
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AUC24h between 48 and 72 h (primary endpoint) and between 72 and 96 h (secondary endpoint) will be estimated for patients in the comparator arm and interventional arm;
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The cumulative AUC (tertiary endpoint) in the comparator arm and interventional arm will be estimated from start until 48 h after stopping treatment;
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The proportion of time within a target AUC24h of 400-600 (secondary endpoint) in the comparator arm and interventional arm will be estimated from start until stop treatment.
End of trial assessments
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Safety assessments;
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Whether or not the patient is (still) receiving vancomycin;
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The date and reason for end of trial including protocol completion, patient death or patient withdrawal of informed consent.
Plans to promote participant retention and complete follow-up {18b}
Data management {19}
Source data
Electronic case report forms (eCRF)
Data handling and record keeping
Confidentiality {27}
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Primary outcome analysis
Secondary outcome analysis
Interim analyses {21b}
Methods for additional analyses (e.g., subgroup analyses) {20b}
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Plans to give access to the full protocol, participant-level data, and statistical code {31c}
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
Local principal investigators (local PI)
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Checking for reportable events during the study period intervention and follow-up;
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Using medical judgment in assigning seriousness, causality, and expectedness using the Reference Safety Information approved for the trial and in consultation with the sub-investigator(s);
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Ensure that reportable events are recorded and reported in line with the requirements of the protocol;
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Checking research protocol compliance.
Medical principal investigator (medical PI)
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Checking for reportable events during the study period intervention and follow-up;
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Ensure that reportable events are recorded and reported in line with the requirements of the protocol;
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Checking research protocol compliance;
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Clinical oversight of the safety of patients participating in the trial, including an ongoing review of the risk/benefit;
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Using medical judgment in assigning seriousness, causality, and expectedness of SAEs/SARs where it has not been possible to obtain local medical assessment;
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Immediate review of all SUSARs;
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Review of specific SAEs and SARs in accordance with the trial risk assessment and protocol as detailed in the trial monitoring plan;
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Assigning Medical Dictionary for Regulatory Activities (MedDRA) or body system coding to all SAEs and SARs;
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Preparing of the annual progress report, including safety summary and deviations in close collaboration with the trial manager and CI;
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Preparing the clinical sections and final sign off of the Development Safety Update Report (DSUR).
Chief investigator (CI)
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Trial coordination in close collaboration with the trial manager;
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Responsible for training end-users on software;
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Registration of end-users, in collaboration with the trial manager;
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Immediate review of all SUSARs, in close interaction with the MPI;
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Review of specific SAEs and SARs in accordance with the trial risk assessment and protocol as detailed in the trial monitoring plan;
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Preparing of the annual progress report, including safety summary and deviations in close collaboration with the trial manager and MPI.
Sponsor—Ghent University Hospital
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Central data collection and verification of reportable events in the eCRF;
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Expedited reporting of SUSARs to the Federal Agency for Medicines and Health Products (FAMHP) and Ethics Committee (EC) within required timelines;
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Notifying investigators of SUSARs that occur within the trial;
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Checking for (annually) and notifying PIs of updates to the Reference Safety Information for the trial;
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Preparing standard tables and other relevant information for the DSUR in collaboration with the CI and ensuring timely submission to the FAMHP and REC;
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Submission of the annual progress reports, including safety summaries and deviations.
Trial manager
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Coordinating role during study recruitment;
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Development of the eCRF and the database based on the protocol;
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Program complex edit checks to check for inconsistencies within the data;
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Check of data entries and clarify any errors and inconsistencies;
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Conduct automatic transfer of data from the MIPD tool to the eCRF.
Study coordinators
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Coordinating role in obtaining informed consent from the participants;
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Patient screening according to the inclusion and exclusion criteria, in collaboration with physician and clinical pharmacist.
Composition of the data monitoring committee, its role and reporting structure {21a}
Adverse event reporting and harms {22}
Safety assessments
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KDIGO stage 3 of AKI;
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Vancomycin infusion reaction (“red man syndrome”).