Colistin Methanesulfonate Sodium Inhalation for Prophylaxis of Ventilator-Associated Pneumonia (CIVAP): A Prospective, Multicentre, Double-Blind, Randomized, Placebo-Controlled Trial

NCT06834971 | Recruiting DMC

• 1 other identifier: Qilu Wang Hao
• Study Type: interventional
• Target: 508
• Locations: 1 country
• Sites: 1

Brief Summary

Previous studies have identified Acinetobacter baumannii (AB), Pseudomonas aeruginosa (PA), and Klebsiella pneumoniae (KP) as the predominant pathogens responsible for ventilator-associated pneumonia (VAP). The challenge of drug resistance, especially against carbapenem is intensifying, with variations noted across different regions. Multidrug-resistant organisms associated VAP (MDR-VAP) are increasing in frequency and are associated with significant morbidity, mortality, therefore imposes a heavy burden on the healthcare system. Colistin methanesulfonate sodium (CMS) has shown effectiveness against gram-negative bacteria, including carbapenem-resistant organisms (CRO) such as carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Klebsiella pneumoniae (CRKP). This trial aims to evaluate the efficacy of a 3-day course of inhaled CMS in lowering the incidence of VAP among patients undergoing invasive mechanical ventilation for at least two days and at high risk of MDR-VAP.

Conditions

Ventilator-Associated Pneumonia (VAP)

Keywords

colistin; prevention; nebulization

Outcome Measures

Primary Outcomes (1)

• The incidence of a first VAP episode from randomization to day 28

  calculated as the ratio of the number of patients diagnosed VAP divided by the number of randomized patients in each group

  from randomization to day 28

Secondary Outcomes (10)

• incidence of a first MDR-VAP episode from randomization to day 28

  from randomization to day 28

• Incidence density of adjudicated VAP from randomisation to day 28

  from randomization to day 28

• Incidence of gram-negative bacteria-related VAP with in vitro susceptibility to CMS from randomisation to day 28

  from randomization to day 28

• The number of antibiotic-days from randomisation to day 28

  from randomization to day 28

• The number of days of mechanical ventilation from randomization to day 28

  from randomization to extubation or day 28, whichever occurs first

Study Arms (2)

CMS group

EXPERIMENTAL

Participants were randomly assigned to receive either CMS (75mg caculated as colistin base activity(CBA), solubilized in 4 mL 0.9% saline) twice daily. Nebulization will be performed using a vibrating mesh nebulizer (Aeroneb solo, Aerogen, Galway, Ireland) placed in the inspiratory limb of the ventilator tubing, behind the Y-piece, and continued until the nebulizer deposit becomes dry for three consecutive days of mechanical ventilation. To ensure the experiment is conducted under blind conditions, the Nebulizer will be covered with an opaque protective cover. A filter will be placed on the expiratory limb to protect the ventilator.

Drug: Colistimethate sodium (CMS)

NS group

NO INTERVENTION

Participants were randomly assigned to receive equivalent volume of 0.9% saline (NS group), twice daily. Nebulization will be performed using a vibrating mesh nebulizer (Aeroneb solo, Aerogen, Galway, Ireland) placed in the inspiratory limb of the ventilator tubing, behind the Y-piece, and continued until the nebulizer deposit becomes dry for three consecutive days of mechanical ventilation. To ensure the experiment is conducted under blind conditions, the Nebulizer will be covered with an opaque protective cover. A filter will be placed on the expiratory limb to protect the ventilator.

Interventions

Colistimethate sodium (CMS) DRUG

CMS (colistimethate sodium, 75mg, solubilized in 4 mL 0.9% saline), twice daily. Nebulization will be performed using a vibrating mesh nebulizer (Aeroneb solo, Aerogen, Galway, Ireland) placed in the inspiratory limb of the ventilator tubing, behind the Y-piece, and continued until the nebulizer deposit becomes dry for three consecutive days of mechanical ventilation. To ensure the experiment is conducted under blind conditions, the Nebulizer will be covered by stickers. A filter will be placed on the expiratory limb to protect the ventilator.

CMS group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

Participants will be enrolled if they meet the following criteria: 1. Age ≥18 years; 2. Mechanical ventilation for more than two consecutive days (48 hours); 3. Patient has high-risk factors for multidrug-resistant bacterial infections, which meet any of the following criteria: (1)History of antibiotic exposure within 30 days; (2)Hospitalization time\>5 days (120 hours); (3)Septic shock; (4) ARDS; (5)Accept renal replacement therapy; (6)Previous colonization of multidrug-resistant bacteria; 4. Informed consent of the patient or a proxy was written. Participants will be excluded in case of: 1. Suspected or confirmed VAP at the inclusion day; 2. Patient ventilated through an endotracheal tube for more than four consecutive days (96 hours); 3. Expected that endotracheal intubation will be removed within the next 24 hours; 4. Tracheostomy; 5. Allergy to CMS; 6. Patients has polymyxins medication history within 7 days or clinical indication for systemic CMS therapy at the inclusion day; 7. Chronic kidney failure with baseline glomerular filtration ≤30 mL/min or Stage 3 classification AKI (KDIGO) (excluding patients undergoing renal replacement therapy); 8. Expected survival time not exceeding 48 hours; 9. Pregnancy or breastfeeding period; 10. Patients previously included in this study or are using any inhaled antibiotics or are participating in other clinical studies within 30 days.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Qilu Hospital of Shandong University: lead

Study Sites (1)

Qilu Hospital of Shandong university

Jinan, Shandong, 250000, China

RECRUITING

Related Publications (13)

• Wu Z, Zhang S, Cao Y, Wang Q, Sun K, Zheng X. Comparison of the clinical efficacy and toxicity of nebulized polymyxin monotherapy and combined intravenous and nebulized polymyxin for the treatment of ventilator-associated pneumonia caused by carbapenem-resistant gram-negative bacteria: a retrospective cohort study. Front Pharmacol. 2023 Aug 16;14:1209063. doi: 10.3389/fphar.2023.1209063. eCollection 2023.

  PMID: 37663252 BACKGROUND

• Povoa FCC, Cardinal-Fernandez P, Maia IS, Reboredo MM, Pinheiro BV. Effect of antibiotics administered via the respiratory tract in the prevention of ventilator-associated pneumonia: A systematic review and meta-analysis. J Crit Care. 2018 Feb;43:240-245. doi: 10.1016/j.jcrc.2017.09.019. Epub 2017 Sep 18.

  PMID: 28942198 BACKGROUND

• Lu Q, Luo R, Bodin L, Yang J, Zahr N, Aubry A, Golmard JL, Rouby JJ; Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Anesthesiology. 2012 Dec;117(6):1335-47. doi: 10.1097/ALN.0b013e31827515de.

  PMID: 23132092 BACKGROUND

• Biswas S, Brunel JM, Dubus JC, Reynaud-Gaubert M, Rolain JM. Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti Infect Ther. 2012 Aug;10(8):917-34. doi: 10.1586/eri.12.78.

  PMID: 23030331 BACKGROUND

• Yu Z, Qin W, Lin J, Fang S, Qiu J. Antibacterial mechanisms of polymyxin and bacterial resistance. Biomed Res Int. 2015;2015:679109. doi: 10.1155/2015/679109. Epub 2015 Jan 15.

  PMID: 25664322 BACKGROUND

• Zhang X, Cui X, Jiang M, Huang S, Yang M. Nebulized colistin as the adjunctive treatment for ventilator-associated pneumonia: A systematic review and meta-analysis. J Crit Care. 2023 Oct;77:154315. doi: 10.1016/j.jcrc.2023.154315. Epub 2023 Apr 28.

  PMID: 37120926 BACKGROUND

• Hu JN, Hu SQ, Li ZL, Bao C, Liu Q, Liu C, Xu SY. Risk factors of multidrug-resistant bacteria infection in patients with ventilator-associated pneumonia: A systematic review and meta-analysis. J Infect Chemother. 2023 Oct;29(10):942-947. doi: 10.1016/j.jiac.2023.06.008. Epub 2023 Jun 13.

  PMID: 37321291 BACKGROUND

• Ranzani OT, Niederman MS, Torres A. Ventilator-associated pneumonia. Intensive Care Med. 2022 Sep;48(9):1222-1226. doi: 10.1007/s00134-022-06773-3. Epub 2022 Jun 30. No abstract available.

  PMID: 35771252 BACKGROUND

• Xie J, Yang Y, Huang Y, Kang Y, Xu Y, Ma X, Wang X, Liu J, Wu D, Tang Y, Qin B, Guan X, Li J, Yu K, Liu D, Yan J, Qiu H. The Current Epidemiological Landscape of Ventilator-associated Pneumonia in the Intensive Care Unit: A Multicenter Prospective Observational Study in China. Clin Infect Dis. 2018 Nov 13;67(suppl_2):S153-S161. doi: 10.1093/cid/ciy692.

  PMID: 30423055 BACKGROUND

• Ding X, Ma X, Gao S, Su L, Shan G, Hu Y, Chen J, Ma D, Zhang F, Zhu W, Sun G, Meng X, Ma L, Zhou X, Liu D, Du B; China National Critical Care Quality Control Center Group. Effect of ICU quality control indicators on VAP incidence rate and mortality: a retrospective study of 1267 hospitals in China. Crit Care. 2022 Dec 29;26(1):405. doi: 10.1186/s13054-022-04285-6.

  PMID: 36581952 BACKGROUND

• Ehrmann S, Barbier F, Demiselle J, Quenot JP, Herbrecht JE, Roux D, Lacherade JC, Landais M, Seguin P, Schnell D, Veinstein A, Gouin P, Lasocki S, Lu Q, Beduneau G, Ferrandiere M, Plantefeve G, Dahyot-Fizelier C, Chebib N, Mercier E, Heuze-Vourc'h N, Respaud R, Gregoire N, Garot D, Nay MA, Meziani F, Andreu P, Clere-Jehl R, Zucman N, Azais MA, Saint-Martin M, Gandonniere CS, Benzekri D, Merdji H, Tavernier E; Reva and CRICS-TRIGGERSEP F-CRIN Research Networks. Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia. N Engl J Med. 2023 Nov 30;389(22):2052-2062. doi: 10.1056/NEJMoa2310307. Epub 2023 Oct 25.

  PMID: 37888914 BACKGROUND

• Papazian L, Klompas M, Luyt CE. Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med. 2020 May;46(5):888-906. doi: 10.1007/s00134-020-05980-0. Epub 2020 Mar 10.

  PMID: 32157357 BACKGROUND

• Metersky ML, Kalil AC. Management of Ventilator-Associated Pneumonia: Guidelines. Infect Dis Clin North Am. 2024 Mar;38(1):87-101. doi: 10.1016/j.idc.2023.12.004.

  PMID: 38280768 BACKGROUND

MeSH Terms

Conditions

Pneumonia, Ventilator-Associated

Interventions

colistinmethanesulfonic acid

Condition Hierarchy (Ancestors)

Healthcare-Associated Pneumonia; Cross Infection; Infections; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Hao Wang, Professor

  Qilu Hospital of Shandong University

  STUDY DIRECTOR

Central Study Contacts

Hao Wang, Professor

CONTACT

18560081013; wanghao34@126.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: professor

Study Record Dates

• First Submitted: February 13, 2025
• First Posted: February 19, 2025
• Study Start: July 15, 2025
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: July 15, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Study protocol and ICF will be shared with other researchers when start this trial for five years.
• Access Criteria: Ever researchers can access our study protocol and ICF from the web of clinical trials.gov.

Locations

CN (1)