Clinical trial NCT06134492: Acyclovir in Ventilated Patients With Pneumonia and HSV-1 in BAL
Official title: Effect of Acyclovir Therapy on the Outcome of Ventilated Patients With Lower Respiratory Tract Infection and Detection of Herpes Simplex Virus in Bronchoalveolar Lavage
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Pneumonia, Viral
Ventilator Associated Pneumonia
Community-acquired Pneumonia
Herpes Simplex
Hospital-acquired Pneumonia
Keywords: Pneumonia
Herpes Simplex
Mechanical Ventilation
Aciclovir
Lead sponsor: Jena University Hospital
Sponsor class: OTHER
First posted: 2023-11-18
Enrollment: 616
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Almost 90 out of 100 people carry herpes simplex viruses (HSV). Once a person has been infected with the herpes viruses, he or she can't get rid of them for the rest of her/his life. For the most part, the viruses are in a dormant state. Only when the immune system is weakened, for example in the case of a serious illness or stress, are the viruses reactivated. They then mainly cause cold sores, which are harmless for healthy people and usually heal without therapy. However, especially in people with a weakened immune system, HSV can also cause serious infections, such as meningitis. In almost every second mechanically ventilated patient in intensive care who has pneumonia, HSV can be detected in the respiratory tract. This is caused by reactivation of the viruses as a result of the severe underlying disease and stress during intensive care therapy. Whether treatment of the herpes viruses (e.g. with acyclovir) is necessary in this situation and helps the patients to cure has not been clarified, especially as acyclovir can also cause side effects such as a deterioration in kidney function. Currently, the physicians decide to treat the herpes viruses in about half of the patients. Several studies have shown that patients for whom the physician decided to treat the viruses survived more often. However, all of these studies looked at the course of the disease only retrospectively and thus are subject to many biases (including physician selection of who receives treatment, missing data). A definitive conclusion as to whether herpesvirus therapy can be recommended cannot be drawn without doubt from these studies. Therefore, the investigators would like to investigate in a randomized controlled trial, i.e. patients are randomly assigned to the experimental (therapy of herpesviruses) or control group (no therapy of herpesviruses), the effect of therapy with acyclovir on survival in ventilated intensive care patients with lower respiratory tract infection (pneumonia) in whom a large amount of HSV was found in the respiratory tract. The goal of the study is to provide clarity on whether therapy will help patients recover.

Detailed description: Herpes-simplex virus (HSV) can be detected in the bronchoalveolar lavage (BAL) in up to 60% of mechanically ventilated (MV) ICU patients with a lower respiratory tract infection (LRTI), depending on the study population and the severity of disease. However, it remains unclear whether the detection represents a harmless viral shedding as a consequence of reactivation, reflecting the severity of the underlying disease and immunoparalysis, or a true clinical infection requiring antiviral therapy. To date, only retrospective studies have investigated the benefit of an antiviral therapy in HSV-positive ICU patients on mechanical ventilation (MV) with LRTI. In a retrospective study and additional meta-analysis on this topic a antiviral treatment was associated with an improved patient outcome, i.e.; lower all-cause hospital mortality (RR 0.74, 95% CI 0.64-0.85) and lower 30-day all-cause mortality (RR 0.75, 95% CI 0.59-0.94; 3 studies). Aim of this study is to determine prospectively in a multicenter, randomized controlled trial whether acyclovir therapy improves outcome in ventilated ICU patients with a LRTI and HSV detection in BAL. Overall, 616 ICU patients with MV and LRTI and HSV1-PCR-detection in BAL (\>= 10E3 copies/ml) will be either randomized to receive acyclovir (10mg/kg body weight tid) for 10 days (or discharge from ICU if this is earlier) or no antiviral therapy (control group). Primary efficacy endpoint will be overall survival within 30 days comparing the acyclovir therapy and the control group. Secondary endpoints include ventilation-free days up to day 30, vasopressor-free days until day 30 and safety.

Eligibility criteria: Inclusion Criteria:

1. ≥ 18 years
2. need for invasive or non-invasive respiratory support
3. PCR HSV-1 detection in BAL (≥ 10\^3 copies/ml)
4. Pneumonia (community or healthcare acquired, incl. ventilator-associated pneumonia)
5. declaration of consent by the patient or legal representative

Exclusion Criteria:

1. History of hypersensitivity to acyclovir or valacyclovir or other components of the investigational product.
2. Pregnancy/Lactation
3. Simultaneous participation in another interventional clinical trial
4. Decision to withhold life-sustaining therapies
5. Use of a virostatic agent (i.v. or p. os) with activity against herpes simplex (acyclovir, valacyclovir, famciclovir/penciclovir, brivudine, cidofovir, foscarnet) for therapeutic or prophylactic reasons at the time of randomization.
6. Solid organ transplantation, stem cell transplantation
7. Neutropenia (absolute neutrophil count \<1500/μl (\<1.5 × 109 /l)
8. Previous study participation in HerpMV

Primary outcomes:
measure: mortality (survival status)
timeFrame: day 30
Secondary outcomes:
measure: Ventilation-free days
timeFrame: day 30
measure: Vasopressor-free days
timeFrame: day 30
measure: Delta SOFA score (Sepsis-related Organ Failure Assessment Score)
timeFrame: Baseline - Day 10 or EOT if this event occurs earlier
measure: Delta SOFA sub-score kidney (Sepsis-related Organ Failure Assessment Score)
timeFrame: Baseline - Day 10 or EOT if this event occurs earlier
measure: Delta GFR value
timeFrame: Baseline - Day 10 or EOT if this event occurs earlier
measure: Length of stay in ICU
timeFrame: day 30
measure: Length of stay in Hospital
timeFrame: day 30
measure: Cost of intervention
timeFrame: up to day 90
measure: Days without delirium/coma
timeFrame: Until day 10 or until EOT if this event occurs earlier
measure: Microbiological cure (EOT)
timeFrame: At day 10 or day of EOT if this event occurs earlier
measure: mortality (survival status)
timeFrame: 90 days
measure: mortality (survival status)
timeFrame: 180 days
measure: Quality of life (EQ-5D-5L)
timeFrame: Measurement at day 10 or EOT if this event occurs earlier, day 30, day 90, and day 180
measure: Incidence SAEs
timeFrame: From time of randomization until day 10 or EOT if this event occurs earlier
Other outcomes:
Locations:
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
state: Baden-Württemberg
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
state: Baden-Württemberg
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
state: Bayern
city: München
country: Germany
facility: Klinikum der Ludwig-Maximilian-Universität München
state: Bayern
city: München
country: Germany
facility: Klinikum rechts der Isar
state: Bayern
city: München
country: Germany
facility: Klinikum rechts der Isar
state: Bayern
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg, Campus Nord
state: Bayern
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg, Campus Süd
state: Bayern
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
state: Bayern
city: Rosenheim
country: Germany
facility: RoMed Klinikum Rosenheim
state: Bayern
city: Herne
country: Germany
facility: Marien Hospital Herne, Universitätsklinikum der Ruhr-Universität Bochum
state: Nordreihn-Westfalen
city: Bielefeld
country: Germany
facility: Evangelisches Klinikum Bethel
state: Nordrhein-Westfalen
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
state: Nordrhein-Westfalen
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Universitätsklinikum Essen
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: Universitätsklinikum Köln AöR
state: Nordrhein-Westfalen
city: Münster
country: Germany
facility: Universitätsklinikum Münster
state: Nordrhein-Westfalen
city: Halle
country: Germany
facility: Universitätsklinikum Halle
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
state: Sachsen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Campus Kiel
state: Schleswig-Holstein
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Campus Lübeck
state: Schleswig-Holstein
city: Jena
country: Germany
facility: Universitätsklinikum Jena
state: Thüringen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
Study officials:
References: