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

Sponsor

Jena University Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06134492

Collaborator

(none)

710

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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 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.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia, Viral Ventilator Associated Pneumonia Community-acquired Pneumonia Herpes Simplex Hospital-acquired Pneumonia	Drug: Acyclovir	Phase 3

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 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

710 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Jan 1, 2024

Anticipated Primary Completion Date :

Jul 1, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment group Aciclovir therapy	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.) Other Names: Aciclovir
No Intervention: Comparison group No study-specific treatment measures

Arm

Intervention/Treatment

Experimental: Treatment group

Aciclovir therapy

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.)

Other Names:

Aciclovir

No Intervention: Comparison group

No study-specific treatment measures

Outcome Measures

Primary Outcome Measures

mortality (survival status) [day 30]
survival status

Secondary Outcome Measures

Ventilation-free days [day 30]
days without mechanically ventilation via endotracheal tube, incl. tracheostoma
Vasopressor-free days [day 30]
days without continuous vasopressor administration > 1h/day
Delta SOFA score (Sepsis-related Organ Failure Assessment Score) [Baseline - Day 10 or EOT if this event occurs earlier]
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
Delta SOFA sub-score kidney (Sepsis-related Organ Failure Assessment Score) [Baseline - Day 10 or EOT if this event occurs earlier]
Sub-score for kidney function, the score ranges from 0 (normal) to 4 (most abnormal)
Delta GFR value [Baseline - Day 10 or EOT if this event occurs earlier]
GFR value
Length of stay in ICU [day 30]
days LOS in ICU
Length of stay in Hospital [day 30]
days LOS in hospital
Cost of intervention [up to day 90]
ICU and hospitalization days + acyclovir
Days without delirium/coma [Until day 10 or until EOT if this event occurs earlier]
based on CAM-ICU / RASS
Microbiological cure (EOT) [At day 10 or day of EOT if this event occurs earlier]
Percent of participants with HSV eradication (PCR testing negative) in blood and respiratory tract
mortality (survival status) [90 days]
survival status
mortality (survival status) [180 days]
survival status
Quality of life (EQ-5D-5L) [Measurement at day 10 or EOT if this event occurs earlier, day 30, day 90, and day 180]
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.
Incidence SAEs [From time of randomization until day 10 or EOT if this event occurs earlier]
Incidence of serious adverse events

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

≥ 18 years
Invasive ventilation expected for ≥ 48 hours from time of randomization
PCR HSV-1 detection in BAL (>=10E5 copies/ml).
Pneumonia (community or healthcare acquired, incl. ventilator-associated pneumonia)
Written declaration of consent by the patient or legal representative

Exclusion Criteria:

History of hypersensitivity to acyclovir or valacyclovir or other components of the investigational product.
Pregnancy/Lactation
Simultaneous participation in another interventional clinical trial
Decision to withhold life-sustaining therapies
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.
Solid organ transplantation, stem cell transplantation
Neutropenia (absolute neutrophil count <1500/μl (<1.5 × 109 /l)
Previous study participation in HerpMV