ORal Antibiotics in Acute Mesenteric Ischemia (ORIAMI)

ORal Antibiotics in Acute Mesenteric Ischemia: a Multicenter Randomized Controlled Trial

Acute mesenteric ischemia (AMI) is a life-threatening condition with an increasing incidence (7-13/100000 PY). The mortality of AMI is associated with the development and extent of transmural intestinal necrosis (IN), ranging from 25% without IN to 75% with IN. Given its potential reversibility, preventing the progression of AMI towards IN is now considered a primary therapeutic goal. Early management of AMI can thus avoid fatal outcomes and prevent lifelong complications such as short bowel syndrome. Following the results of a pilot study showing an improvement in survival and lower resection rates, our team created a first-of-its-kind intestinal stroke center (SURVI unit, Beaujon Hospital, Clichy, France) that provides 24/7 standardized multimodal and multidisciplinary care to AMI patients referred from all hospitals in the Paris region. As no randomized clinical trial has ever been conducted, the treatment offered by SURVI is based on pathophysiological knowledge and observational clinical data. AMI naturally progresses to sepsis, surgical complications, and multi-organ failure, direct consequences of IN. Features of sepsis are reported in up to 90% of AMI patients compared with 3-22% of patients with brain or myocardial ischemia, supporting a specific septic component in AMI. Experimental studies demonstrated reduced translocation and mortality in germ-free animals or after administration of oral antibiotics targeting Gram-negative and anaerobic early bacterial overgrowth and translocation. In a prospective observational study, the investigators recently suggested a protective effect of systematic oral antibiotics in terms of intestinal preservation, yielding a reduced occurrence of IN (HR: 0.16, 95% confidence interval 0.03-0.62). However, the systematic use of oral antibiotics in AMI remains controversial due to the individual and collective risk of increasing the carriage of multi-drug resistant bacterias.

Study Overview

• Status: Recruiting
• Conditions: Acute Mesenteric Ischemia
• Intervention / Treatment: Drug: Gentamicin; Drug: Metronidazole; Drug: Placebo

Detailed Description

After the screening visit and informed consent collected by the recruiting investigator, all consecutive eligible patients (who will meet all inclusion criteria and none of exclusion criteria) will be included and randomized double-blind to oral antibiotics or double placebo group.

Patients will be evaluated at days 1, 3, 7, 14, 21 and 30 after the randomisation.

• Study Type: Interventional
• Enrollment (Estimated): 196
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alexandre NUZZO, Dr; Phone Number: (0)1 40 87 56 57; Email: alexandre.nuzzo@aphp.fr
• Study Contact Backup: Name: Olivier CORCOS, Pr; Phone Number: (0)1 40 87 56 95; Email: olivier.corcos@aphp.fr

Study Locations

• France
  • Clichy, France, 92110
    • Recruiting
    • Gastroentérologie-Hépatologie Beaujon
    • Contact: Alexandre NUZZO, Dr; Phone Number: (0)1 40 87 56 57; Email: alexandre.nuzzo@aphp.fr
  • Clichy, France, 92110
    • Recruiting
    • Réanimation - Beaujon
    • Contact: Emmanuel WEISS, Dr; Email: emmanuel.weiss@aphp.fr
  • Paris, France, 75018
    • Not yet recruiting
    • Chirurgie vasculaire
    • Contact: Yves Hervé CASTIER; Email: yves.castier@aphp.fr
  • Paris, France, 75018
    • Not yet recruiting
    • Réanimation Bichat
    • Contact: Brice LORTAT JACOB, Dr; Email: brice.lortat-jacob@aphp.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adult patient aged 18 and less 90

• AMI of arterial occlusive origin, defined by the combination of

  1. Onset < 7 days of clinical, biological and/or radiological signs of acute intestinal injury in the territory of at least superior mesenteric ischemia, including right-side colitis,
  2. significant vascular obstruction > 75% of the superior mesenteric artery, and
  3. no alternative diagnosis
• Admitted to the SURVI care network (Beaujon Hospital intensive care unit or SURVI, Bichat intensive care unit or vascular surgery department)

Exclusion Criteria:

• Other forms of mesenteric ischemia (chronic without acute manifestations, venous, non-occlusive, strangulation, aortic dissection)
• Isolated left-side ischemic colitis
• Mesenteric vascular lesion without small bowel injury or right colon
• Not eligible for vascular or digestive surgery or intensive care (palliative context)
• Indication for an emergency surgical intestinal resection at the admission to the SURVI care network
• Indication for urgent systemic antibiotic treatment on admission (evidence of sepsis defined as a SOFA score of 2 or more associated with an infection)
• Systemic or oral antibiotic therapy within 7 days before inclusion
• Known hypersensitivity to the active substance /excipients
• Contraindications to the investigational medicinal products (gentamicin, metronidazole)
• Unable to give consent (under guardianship or curatorship)
• Subject deprived of freedom, subject under a legal protective measure
• Patient refusal to participate
• Non-affiliation to a social security regimen or CMU
• Patient under State Medical Aid
• Pregnant or breastfeeding women
• Participation in another clinical study involving investigational medicinal product or patient being in the exclusion period at the end of a previous study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gentamicin + Metronidazole; Gentamicin 80 mg Metronidazole 500mg 3 times per day during 14 days oral route or nasogastric tube or jejunostomy tube (in the case of an ostomy)	Drug: Gentamicin; Gentamicin 80 mg 3 times per day during 14 days oral route or nasogastric tube or jejunostomy tube (in the case of an ostomy); Drug: Metronidazole; Métronidazole 500mg 3 times per day during 14 days oral route or nasogastric tube or jejunostomy tube (in the case of an ostomy)
Placebo Comparator: Placebo; Gentamicin placebo (2ml sodium chloride diluted 1/10 in a syringe of 20mL Metronidazole placebo in tablets	Drug: Placebo; Gentamicin placebo (2ml sodium chloride diluted 1/10 in a syringe of 20mL Metronidazole placebo in tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary objective is to assess the efficacy of oral antibiotics compared to placebo on reducing the rate of intestinal necrosis or death (composite primary outcome) in AMI patients within 30 days following the randomisation.	Occurrence of intestinal necrosis or death within 30 days following randomisation defined by the following criteria histology assessment OR all-cause mortality within 30 days following randomisation	30 days after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the rate of intestinal necrosis in the 30 days following the randomisation	occurrence of intestinal necrosis within the 30 days following the randomisation.	30 days after randomisation
the rate of short bowel syndrome (<200cm of remnant small bowel) at day-30 following the randomisation	short bowel syndrome at day-30 after the randomisation	30 days after randomisation
the length of intestinal resection at day-30 following the randomisation	total length of intestinal resection at day 30 following the randomisation	30 days after randomisation
the occurrence of organ failures within the 30 days following the randomisation	occurrence of organ failure within the 30 days following the randomisation	30 days after randomisation
the length of ICU stay	number of days in the intensive care unit	30 days after randomisation
the length of hospital stay	number of hospitalization days	30 days after randomisation
expected minor side effects during the 14 days of treatment	Occurrence of minor side effects	14 days after randomisation
hypersensitivity reactions during the 14 days of treatment	Occurrence of hypersensitivity reaction to antibiotics	14 days after randomisation
unexpected or serious adverse event throughout the duration of the study	Occurrence of other adverse events	30 days after randomisation
the occurrence of healthcare-associated infection	Occurrence of healthcare-associated infection	30 days after randomisation
the gentamicin during the 14 days of treatment	Blood levels of gentamicin at randomisation day , days 7 and 14 after randomisation	14 days after randomisation
the metronidazole during the 14 days of treatment	Blood levels of metronidazole at randomisation day, days 7 and 14 after randomisation	14 days after randomisation

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Chair: Annabelle METOIS, Mrs, APHP

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2025
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: April 17, 2024
• First Submitted That Met QC Criteria: April 23, 2024
• First Posted (Actual): April 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 17, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: necrosis
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Peritoneal Diseases; Ischemia; Mesenteric Ischemia; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Protein Synthesis Inhibitors; Metronidazole; Gentamicins
• Other Study ID Numbers: APHP220818

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No