Acyclovir in Mechanically Ventilated Patients With Pneumonia and HSV-1 in BAL

Ventilator Associated Pneumonia Clinical Trial

— HerpMV  

Official title:

Effect of Acyclovir Therapy on the Outcome of Mechanically Ventilated Patients With Lower Respiratory Tract Infection and Detection of Herpes Simplex Virus in Bronchoalveolar Lavage

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06134492
• Other study ID #: ZKSJ0153
• Secondary ID: BMBF 01KG2301
• Status: Recruiting
• Phase: Phase 3
• Start date: February 20, 2024
• Est. completion date: December 2026

Study information

• Verified date: April 2024
• Source: Jena University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 mechanically 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.

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 mechanically ventilated ICU patients with a LRTI and HSV detection in BAL. Overall, 710 ICU patients with MV and LRTI and HSV1-PCR-detection in BAL (>= 10E5 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 710
• Est. completion date: December 2026
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. = 18 years

2. Invasive ventilation expected for = 48 hours from time of randomization

3. PCR HSV-1 detection in BAL (>=10E5 copies/ml).

4. Pneumonia (community or healthcare acquired, incl. ventilator-associated pneumonia)

5. Written 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 (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

Related Conditions & MeSH terms

• Community-acquired Pneumonia
• Healthcare-Associated Pneumonia
• Herpes Simplex
• Hospital-acquired Pneumonia
• Pneumonia
• Pneumonia, Ventilator-Associated
• Pneumonia, Viral
• Ventilator Associated Pneumonia

Intervention

Drug:
• Acyclovir
Dosage: 10mg/kg (current) body weight every 8 hours, dose adjustment to renal function according to technical information. Mode of administration: intravenous (i.v.)

Locations

Country	Name	City	State
Germany	Universitätsklinikum Augsburg	Augsburg	Bayern
Germany	Evangelisches Klinikum Bethel	Bielefeld	Nordrhein-Westfalen
Germany	Universitätsklinikum Bonn	Bonn	Nordrhein-Westfalen
Germany	Universitätsklinikum Dresden	Dresden	Sachsen
Germany	Universitätsklinikum Düsseldorf	Düsseldorf	Nordrhein-Westfalen
Germany	Universitätsklinikum Essen	Essen	Nordrhein-Westfalen
Germany	Universitätsklinikum Freiburg	Freiburg	Baden-Württemberg
Germany	SRH Wald Klinikum Gera	Gera	Thüringen
Germany	Universitätsklinikum Halle	Halle	Sachsen-Anhalt
Germany	Universitätsklinikum Hamburg Eppendorf	Hamburg
Germany	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg
Germany	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg
Germany	Marien Hospital Herne, Universitätsklinikum der Ruhr-Universität Bochum	Herne	Nordreihn-Westfalen
Germany	Universitätsklinikum Jena	Jena	Thüringen
Germany	Universitätsklinikum Schleswig-Holstein Campus Kiel	Kiel	Schleswig-Holstein
Germany	Universitätsklinikum Köln AöR	Köln	Nordrhein-Westfalen
Germany	Universitätsklinikum Leipzig	Leipzig	Sachsen
Germany	Universitätsklinikum Leipzig	Leipzig	Sachsen
Germany	Universitätsklinikum Schleswig-Holstein Campus Lübeck	Lübeck	Schleswig-Holstein
Germany	Klinikum der Ludwig-Maximilian-Universität München	München	Bayern
Germany	Klinikum rechts der Isar	München	Bayern
Germany	Klinikum rechts der Isar	München	Bayern
Germany	Universitätsklinikum Münster	Münster	Nordrhein-Westfalen
Germany	Universitätsklinikum Münster	Münster	Nordrhein-Westfalen
Germany	Klinikum Nürnberg, Campus Nord	Nürnberg	Bayern
Germany	Klinikum Nürnberg, Campus Süd	Nürnberg	Bayern
Germany	Universitätsklinikum Regensburg	Regensburg	Bayern
Germany	RoMed Klinikum Rosenheim	Rosenheim	Bayern
Germany	Universitätsklinikum Tübingen	Tübingen	Baden-Württemberg

Sponsors (1)

Lead Sponsor	Collaborator
Jena University Hospital

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	mortality (survival status)	survival status	day 30
Secondary	Ventilation-free days	days without mechanically ventilation via endotracheal tube, incl. tracheostoma	day 30
Secondary	Vasopressor-free days	days without continuous vasopressor administration > 1h/day	day 30
Secondary	Delta SOFA score (Sepsis-related Organ Failure Assessment Score)	Each of six organ systems receive a score ranging from 0 (normal) to 4 (most abnormal), with a minimum SOFA score of 0 and a maximum SOFA score of 24	Baseline - Day 10 or EOT if this event occurs earlier
Secondary	Delta SOFA sub-score kidney (Sepsis-related Organ Failure Assessment Score)	Sub-score for kidney function, the score ranges from 0 (normal) to 4 (most abnormal)	Baseline - Day 10 or EOT if this event occurs earlier
Secondary	Delta GFR value	GFR value	Baseline - Day 10 or EOT if this event occurs earlier
Secondary	Length of stay in ICU	days LOS in ICU	day 30
Secondary	Length of stay in Hospital	days LOS in hospital	day 30
Secondary	Cost of intervention	ICU and hospitalization days + acyclovir	up to day 90
Secondary	Days without delirium/coma	based on CAM-ICU / RASS	Until day 10 or until EOT if this event occurs earlier
Secondary	Microbiological cure (EOT)	Percent of participants with HSV eradication (PCR testing negative) in blood and respiratory tract	At day 10 or day of EOT if this event occurs earlier
Secondary	mortality (survival status)	survival status	90 days
Secondary	mortality (survival status)	survival status	180 days
Secondary	Quality of life (EQ-5D-5L)	EuroQuality of Life Five Dimensions (EQ-5D-5L), the descriptive system comprises five dimensions (MOBILITY, SELF-CARE, USUAL ACTIVITIES, PAIN / DISCOMFORT and ANXIETY / DEPRESSION), with five response levels: no problems, slight problems, moderate problems, severe problems, unable to/extreme problems.	Measurement at day 10 or EOT if this event occurs earlier, day 30, day 90, and day 180
Secondary	Incidence SAEs	Incidence of serious adverse events	From time of randomization until day 10 or EOT if this event occurs earlier

External Links

•   Study protocol