Evaluation of Procalcitonin-Guided and Molecular-Guided Therapy with Vaborbactam and Drug Combination in Patients with Severe Infections
- Trial ID
- 2022-502962-26-00
- Protocol
- MODIFY
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the MODIFY trial is to reduce the duration of treatment with empirical broad-spectrum **antibiotics** in patients with severe infections. This is clinically relevant as it aims to minimize the potential adverse effects and resistance associated with prolonged use of broad-spectrum antibiotics, thereby improving patient outcomes and antibiotic stewardship.
Secondary objectives include evaluating the impact of the MODIFY strategy on clinical outcomes, specifically by measuring the time to optimal therapy, changes in the **SOFA** (Sequential Organ Failure Assessment) score, and mortality rates. These secondary objectives are crucial for understanding the broader clinical implications of the MODIFY strategy on patient health and recovery in severe infections.
Participants
The clinical trial focuses on participants diagnosed with **severe infections**, specifically targeting individuals with sepsis as defined by the Sepsis-3 criteria. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a positive blood culture and must provide written informed consent, either personally or through a legal representative if sepsis affects their mental capacity. The trial includes individuals with community-acquired or hospital-acquired infections such as pneumonia, acute pyelonephritis, and primary bacteremia. The selection process ensures that participants have not been hospitalized for more than two days in the last 90 days, are not under hemodialysis, and are not residents of long-term care facilities, unless they meet the criteria for hospital-acquired sepsis. The trial population is characterized by a vulnerable group, and both genders are represented. However, the sponsor has not provided the total number of participants involved in the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, prospective study aimed at evaluating the efficacy of procalcitonin-guidance and molecular-guided diagnosis in the treatment of **severe infections**. The trial employs a **double-blind** methodology to ensure unbiased results, with participants randomly assigned to either the intervention group receiving the MODIFY strategy or the control group receiving standard care. The primary objective is to reduce the duration of treatment with empirical broad-spectrum antibiotics. The trial is expected to run from June 2023 to March 2025, with an estimated duration of 22 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, presence of sepsis as defined by the Sepsis-3 criteria, and a positive blood culture. Following successful screening, participants will be enrolled and randomized into the study. The trial includes several follow-up visits to monitor the treatment's effectiveness and safety, with assessments such as time to first change of antibiotics, time to the first sterile blood culture, and changes in the Sequential Organ Failure Assessment (SOFA) score. The end-of-study visit will occur after the completion of the treatment period, which is a maximum of 10 days, to evaluate the primary and secondary endpoints, including 28-day and 90-day mortality rates, incidence of Clostridioides difficile infection, and length of hospital stay.
Participant involvement is expected to last for the duration of the treatment period, with additional follow-up assessments extending up to 90 days post-treatment. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or any medical condition that, in the investigator's opinion, warrants discontinuation. The trial's design ensures rigorous monitoring and adherence to ethical standards, with informed consent obtained from all participants or their legal representatives.
Treatment
The clinical trial involves the administration of several **experimental medications** and standard-of-care treatments. **Vaborbactam** is administered as a solution for infusion with a maximum daily dose of 6 grams and a total dose of 60 grams over a 10-day period. The route of administration is via **IV infusion**. **Ceftriaxone** is provided as a powder and solvent for solution for injection, with a maximum daily dose of 2 grams and a total dose of 20 grams, administered through **intravenous injection**. **Ceftazidime** is also administered as a solution for infusion, with a maximum daily dose of 6 grams and a total dose of 60 grams, delivered via **IV infusion**.
**Avibactam** is administered as a solution for infusion, with a maximum daily dose of 1.5 grams and a total dose of 15 grams, using the **IV infusion** route. **Cefuroxime** is provided as a powder for solution for injection/infusion, with a maximum daily dose of 4.5 grams and a total dose of 45 grams, administered via **IV infusion**. **Ceftolozane** is administered as a solution for infusion, with a maximum daily dose of 3 grams and a total dose of 30 grams, using the **IV infusion** route.
**Vancomycin** is provided as a powder for solution for infusion, with a maximum daily dose of 2 grams and a total dose of 20 grams, administered via **IV infusion**. **Piperacillin** is administered as a solution for infusion, with a maximum daily dose of 16 grams and a total dose of 160 grams, using the **IV infusion** route. **Imipenem** is administered as a solution for infusion, with a maximum daily dose of 4 grams and a total dose of 40 grams, delivered via **IV infusion**.
**Linezolid** is administered as a solution for infusion, with a maximum daily dose of 1.2 grams and a total dose of 12 grams, using the **IV infusion** route. **Anidulafungin** is provided as a powder for solution for infusion, with a maximum daily dose of 200 mg and a total dose of 1.1 grams, administered via **IV infusion**. **Teicoplanin** is administered as a powder and solvent for solution for injection/infusion, with a maximum daily dose of 12 mg/kg and a total dose of 66 mg/kg, using both **IV injection and IV infusion** routes.
**Colistimethate sodium** is provided as a powder for solution for injection/infusion, with a maximum daily dose of 9,000,000 IU and a total dose of 90,000,000 IU, administered via **IV injection and IV infusion**. **Relebactam** is administered as a solution for infusion, with a maximum daily dose of 1 gram and a total dose of 10 grams, using the **IV infusion** route. **Meropenem** is provided as a powder for solution for injection/infusion, with a maximum daily dose of 6 grams and a total dose of 60 grams, administered via **IV injection and IV infusion**.
**Micafungin** is administered as a powder for solution for infusion, with a maximum daily dose of 150 mg and a total dose of 1.5 grams, using the **IV infusion** route. **Tazobactam** is provided as a solution for infusion, with a maximum daily dose of 2 grams and a total dose of 20 grams, administered via **IV infusion**. The trial also includes the use of standard-of-care antibiotics and antifungals as comparator treatments. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules and administration routes.
Efficacy
The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the number of days patients are treated with broad-spectrum antibiotics in the group receiving the MODIFY strategy compared to those treated with the standard of care. Secondary endpoints include several parameters: time to first change of antibiotics, time to the first sterile blood culture, maintenance of the same antimicrobial(s) in case of activity against the pathogen, at least a 2-point decrease of baseline Sequential Organ Failure Assessment (**SOFA**) score by day 7, 28-day mortality, 90-day mortality, incidence of laboratory-documented Clostridioides difficile infection, length of hospital stay, cost of hospitalization, time to escalation of antibiotics, and time to de-escalation of antibiotics.
These efficacy parameters will be measured and collected at various timepoints throughout the trial. The trial is designed to evaluate the effectiveness of the MODIFY strategy in reducing the duration of broad-spectrum antibiotic treatment and improving patient outcomes in severe infections. The analysis will involve comparing the MODIFY strategy group with the standard care group to determine the impact on the specified endpoints. The trial aims to provide evidence on the potential benefits of procalcitonin-guidance and molecular-guided diagnosis in managing severe infections.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female
- For women of child-bearing potential, willingness to avoid pregnancy during the study and agreement to notify investigator if pregnancy occurs.
- Age more than or equal to 18 years
- Sepsis defined by the Sepsis-3 definition; this is defined separately for community-acquired sepsis and for hospital-acquired sepsis. Community-acquired sepsis is defined as any SOFA score 2 points or more for patients admitted in hospital emergencies with community-acquired pneumonia (CAP), community-acquired acute pyelonephritis (AP) or community-acquired primary bacteremia (BSI). CAP, AP and BSI are considered community-acquired for patients who have no history of hospitalization lasting more than 2 days the last 90 days or who are not under hemodialysis or who are not residents of long-term care facilities. Hospital-acquired sepsis is defined as any SOFA score increase by 2 points or more from the admission SOFA score for patients with onset of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), acute pyelonephritis (AP) or primary bacteremia (BSI) at least 48 hours after hospital admission. For patients with history of hospitalization lasting more than 2 days the last 90 days or who are under hemodialysis or who are residents of long-term care facilities and are admitted to hospital with HAP, VAP, AP and BSI the definition of hospital-acquired sepsis applies. In this case, the baseline SOFA score is considered as the known SOFA score before infection onset.
- Presence of one of the following infections: community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), acute pyelonephritis (AP) and primary bacteremia (BSI).
- Positive blood culture
- Written informed consent provided by the patient or by their legal representative in case of patients unable to consent due to sepsis onset affecting their mental capacity.
- Patients who have completed their participation in another study for more than 30 days can be included in this study.
Exclusion Criteria
- Failure to obtain written consent to participate
- Previous enrollment in this study within the past 90 days. Patients enrolled in another study will not be accepted.
- Patients in pregnancy or breastfeeding. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
- Patients receiving prolonged antibiotic therapies (e.g. endocarditis, implantable device-associated infection, cerebral/hepatic abscess, osteomyelitis, meningitis)
- Patients with severe infections due to viruses or parasites (e.g. Dengue, Toxoplasma gondii, Plasmodium spp.)
- Patients with infection due to Mycobacterium tuberculosis
- Patients suffering from cystic fibrosis
- Severely immunocompromised patients such as a) patients with infection by the human immunodeficiency virus and with a CD4 count of less than 200 cells/mm3; b) neutropenic patients with less than 500 neutrophils/mm3; and c) patients with solid organ transplantation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Greece | Not Recruiting | 01 Jun 2023 | 190 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CEFTOLOZANE | Test | — | IV INFUSION | 3 | 10 | SUB167762 |
CEFTRIAXONE | Test | — | INTRAVENOUS INJECTION | 2 | 10 | SUB07431MIG |
PIPERACILLIN | Comparator | — | IV INFUSION | 16 | 10 | SUB09867MIG |
CEFTOLOZANE | Comparator | — | IV INFUSION | 3 | 10 | SUB167762 |
LINEZOLID | Test | — | IV INFUSION | 1.2 | 10 | SUB08520MIG |
TEICOPLANIN | Comparator | — | IV INFUSION | 12 | 10 | SUB04714MIG |
MEROPENEM | Test | — | IV INJECTION, IV INFUSION | 6 | 10 | SUB08778MIG |
TEICOPLANIN | Test | — | IV INJECTION, IV INFUSION | 12 | 10 | SUB04714MIG |
VABORBACTAM | Comparator | — | IV INFUSION | 6 | 10 | SUB185581 |
TAZOBACTAM | Comparator | — | IV INFUSION | 2 | 10 | SUB10849MIG |