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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Pneumonia, Viral; Hospital-acquired Pneumonia; Herpes Simplex; Ventilator Associated Pneumonia; Community-acquired Pneumonia
• Intervention / Treatment: Drug: Acyclovir

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 Type: Interventional
• Enrollment (Estimated): 710
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • Recruiting
    • Universitätsklinikum Hamburg Eppendorf
    • Contact: Stefan Kluge, Prof. Dr.; Phone Number: 040741057010; Email: s.kluge@uke.de
    • Principal Investigator: Stefan Kluge, Prof. Dr.
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
      • Not yet recruiting
      • Universitätsklinikum Freiburg
      • Contact: Paul Biever, Dr.; Phone Number: 076127034931; Email: paul.biever@uniklinik-freiburg.de
      • Principal Investigator: Paul Biever, Dr.
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Recruiting
      • Universitätsklinikum Heidelberg
      • Contact: Markus Weigand, Prof. Dr.; Phone Number: 06221 56-36351; Email: anae.sekretariat@med.uni-heidelberg.de
      • Principal Investigator: Markus Weigand, Prof. Dr.
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Not yet recruiting
      • Universitätsklinikum Heidelberg
      • Contact: Tobias Gutting, Dr.; Phone Number: 062215637985; Email: tobias.gutting@med.uni-heidelberg.de
      • Principal Investigator: Tobias Gutting, Dr.
    • Tübingen, Baden-Württemberg, Germany, 72076
      • Recruiting
      • Universitätsklinikum Tübingen
      • Contact: Peter Rosenberger, Prof. Dr.; Phone Number: 070712986622; Email: peter.rosenberger@med.uni-tuebingen.de
      • Principal Investigator: Peter Rosenberger, Prof. Dr.
  • Bayern
    • Augsburg, Bayern, Germany, 86156
      • Not yet recruiting
      • Universitätsklinikum Augsburg
      • Contact: Phillip Simon, Prof. Dr.; Phone Number: 08214002378; Email: philipp.simon3@uk-augsburg.de
      • Principal Investigator: Phillip Simon, Prof. Dr.
    • München, Bayern, Germany, 81377
      • Not yet recruiting
      • Klinikum der Ludwig-Maximilian-Universität München
      • Contact: Michael Zoller, Dr.; Phone Number: 015254849023; Email: michael.zoller@med.uni-muenchen.de
      • Principal Investigator: Michael Zoller, Dr.
    • München, Bayern, Germany, 81675
      • Recruiting
      • Klinikum rechts der Isar
      • Contact: Tobias Lahmer, Dr.; Phone Number: 08941409345; Email: tobias.lahmer@mri.tum.de
      • Principal Investigator: Tobias Lahmer, Dr.
    • Nürnberg, Bayern, Germany, 90419
      • Not yet recruiting
      • Klinikum Nürnberg, Campus Nord
      • Contact: Arnim Geise, Dr.; Phone Number: 09113983479; Email: arnim.geise@klinikum-nuernberg.de
      • Principal Investigator: Arnim Geise, Dr.
    • Nürnberg, Bayern, Germany, 90471
      • Recruiting
      • Klinikum Nürnberg, Campus Süd
      • Contact: Silke Fortenbacher, Dr.; Phone Number: 0911398118734; Email: silke.fortenbacher@klinikum-nuernberg.de
      • Principal Investigator: Silke Fortenbacher, Dr.
    • Regensburg, Bayern, Germany, 93053
      • Not yet recruiting
      • Universitätsklinikum Regensburg
      • Contact: Alexander Dejaco, Dr.; Phone Number: 09419447801; Email: alexander.dejaco@klinik.uni-regensburg.de
      • Principal Investigator: Alexander Dejaco, Dr.
    • Rosenheim, Bayern, Germany, 83022
      • Not yet recruiting
      • RoMed Klinikum Rosenheim
      • Contact: Balázs Poros, Dr.; Phone Number: 080313656841; Email: balzs.poros@ro-med.de
      • Principal Investigator: Balázs Poros, Dr.
  • Nordreihn-Westfalen
    • Herne, Nordreihn-Westfalen, Germany, 44625
      • Recruiting
      • Marien Hospital Herne, Universitätsklinikum der Ruhr-Universität Bochum
      • Principal Investigator: Ulrich Frey, Prof. Dr. med.
      • Contact: Ulrich Frey, Prof. Dr.; Phone Number: 023234991575; Email: ulrich.frey@elisabethgruppe.de
  • Nordrhein-Westfalen
    • Bielefeld, Nordrhein-Westfalen, Germany, 33617
      • Not yet recruiting
      • Evangelisches Klinikum Bethel
      • Contact: Friedhelm Bach, Dr.; Phone Number: 052177279107; Email: friedhelm.bach@evkb.de
      • Principal Investigator: Friedhelm Bach, Dr.
    • Bonn, Nordrhein-Westfalen, Germany, 53127
      • Recruiting
      • Universitätsklinikum Bonn
      • Principal Investigator: Christian Putensen, Prof. Dr.
      • Contact: Christian Putensen, Prof. Dr.; Phone Number: 022828714119; Email: putensen@uni-bonn.de
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40225
      • Recruiting
      • Universitätsklinikum Düsseldorf
      • Contact: Christian Jung, Prof. Dr.; Phone Number: 02118118801; Email: christian.jung@med.uni-duesseldorf.de
      • Principal Investigator: Christian Jung, Prof. Dr.
    • Essen, Nordrhein-Westfalen, Germany, 45147
      • Recruiting
      • Universitätsklinikum Essen
      • Principal Investigator: Thorsten Brenner, Prof. Dr. med.
      • Contact: Thorsten Brenner, Prof. Dr.; Phone Number: 0201 723 1401; Email: anaesthesiologie@uk-essen.de
    • Köln, Nordrhein-Westfalen, Germany, 50937
      • Not yet recruiting
      • Universitätsklinikum Köln AöR
      • Contact: Fabian Dusse, Dr.; Phone Number: 022147842113; Email: fabian.dusse@uk-koeln.de
      • Principal Investigator: Fabian Dusse, Dr.
    • Münster, Nordrhein-Westfalen, Germany, 48149
      • Not yet recruiting
      • Universitätsklinikum Münster
      • Contact: Jan-Sören Padberg, Dr.; Phone Number: 02518343247; Email: jan-soeren.padberg@ukmuenster.de
      • Principal Investigator: Jan-Sören Padberg, Dr.
    • Münster, Nordrhein-Westfalen, Germany, 48149
      • Recruiting
      • Universitätsklinikum Münster
      • Principal Investigator: Christian Ertmer, Prof. Dr.
      • Contact: Christian Ertmer, Prof. Dr.; Phone Number: 02518348735; Email: ertmer@anit.uni-muenster.de
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Recruiting
      • Universitätsklinikum Dresden
      • Principal Investigator: Andreas Güldner, Dr. med.
      • Contact: Andreas Güldner, Dr. med.; Phone Number: 035145818493; Email: andreas.gueldner@ukdd.de
    • Leipzig, Sachsen, Germany, 04103
      • Recruiting
      • Universitatsklinikum Leipzig
      • Principal Investigator: Sirak Petros, Prof. Dr.
      • Contact: Sirak Petros, Prof. Dr.; Phone Number: 03419712700; Email: MB-Internistische-Intensivmedizin@medizin.uni-leipzig.de
    • Leipzig, Sachsen, Germany, 04103
      • Not yet recruiting
      • Universitatsklinikum Leipzig
      • Contact: Gunther Hempel, Dr.; Phone Number: 03419717136; Email: studien-kai@medizin.uni-leipzig.de
      • Principal Investigator: Gunther Hempel, Dr.
  • Sachsen-Anhalt
    • Halle, Sachsen-Anhalt, Germany, 06120
      • Recruiting
      • Universitätsklinikum Halle
      • Contact: Alexander Vogt, Dr.; Phone Number: 03455573134; Email: alexander.vogt@uk-halle.de
      • Principal Investigator: Alexander Vogt, Dr.
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Not yet recruiting
      • Universitätsklinikum Schleswig-Holstein Campus Kiel
      • Contact: Matthias Lindner, Dr.; Phone Number: 043150068103; Email: Matthias.Lindner@uksh.de
      • Principal Investigator: Matthias Lindner, Dr.
    • Lübeck, Schleswig-Holstein, Germany, 23538
      • Recruiting
      • Universitätsklinikum Schleswig-Holstein Campus Lübeck
      • Contact: Maria Deja, Prof. Dr.; Phone Number: 045150040710; Email: maria.deja@uksh.de
      • Principal Investigator: Maria Deja, Prof. Dr.
  • Thüringen
    • Gera, Thüringen, Germany, 07548
      • Not yet recruiting
      • SRH Wald Klinikum Gera
      • Contact: Caterina Reuchsel, Dr.; Phone Number: 03658282801; Email: caterina.reuchsel@srh.de
      • Principal Investigator: Caterina Reuchsel, Dr.
    • Jena, Thüringen, Germany, 07747
      • Recruiting
      • Universitätsklinikum Jena
      • Contact: Frank Bloos, PD Dr.; Phone Number: 036419323283; Email: frank.bloos@med.uni-jena.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality (survival status)	survival status	day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilation-free days	days without mechanically ventilation via endotracheal tube, incl. tracheostoma	day 30
Vasopressor-free days	days without continuous vasopressor administration > 1h/day	day 30
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
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
Delta GFR value	GFR value	Baseline - Day 10 or EOT if this event occurs earlier
Length of stay in ICU	days LOS in ICU	day 30
Length of stay in Hospital	days LOS in hospital	day 30
Cost of intervention	ICU and hospitalization days + acyclovir	up to day 90
Days without delirium/coma	based on CAM-ICU / RASS	Until day 10 or until EOT if this event occurs earlier
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
mortality (survival status)	survival status	90 days
mortality (survival status)	survival status	180 days
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
Incidence SAEs	Incidence of serious adverse events	From time of randomization until day 10 or EOT if this event occurs earlier

Collaborators and Investigators

• Sponsor: Jena University Hospital

Publications and helpful links

Helpful Links

• Study protocol

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: November 1, 2023
• First Submitted That Met QC Criteria: November 10, 2023
• First Posted (Actual): November 18, 2023

Study Record Updates

• Last Update Posted (Actual): April 29, 2024
• Last Update Submitted That Met QC Criteria: April 26, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Pneumonia; Mechanical Ventilation; Herpes Simplex; Aciclovir
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; DNA Virus Infections; Cross Infection; Iatrogenic Disease; Skin Diseases, Infectious; Skin Diseases, Viral; Herpesviridae Infections; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Viral; Pneumonia, Ventilator-Associated; Herpes Simplex; Anti-Infective Agents; Antiviral Agents; Acyclovir
• Other Study ID Numbers: ZKSJ0153; BMBF 01KG2301 (Other Grant/Funding Number: Federal Ministry of Education and Research)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Results will be published in a journal indexed in MEDLINE and CTIS; there are no publication restrictions. After publication, deidentified, individual participant data that underlie this trial, along with a data dictionary describing variables in the dataset, will be made available to researchers whose proposed purpose of use is approved by the Trial Management Team.
• IPD Sharing Time Frame: After publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No