Background Patients with type 2 intestinal failure (T2IF) due to double enterostomy or enterocutaneous fistula (DES/ECF) require parenteral nutrition (PN), carrying risks of catheter sepsis, venous thrombosis, and liver disease. Chyme reinfusion therapy (CRT) may reduce PN dependence but has not been evaluated in a randomised controlled trial (RCT). This study assessed whether device-assisted CRT using The Insides System reduces PN requirements.

Methods This multicentre, open-label RCT enrolled PN-dependent adults with T2IF due to DES/ECF across 12 centres in the UK and USA. Patients with insufficient distal limb length, proximal bowel obstruction, active sepsis, or severe hepatorenal failure were excluded. Participants were block randomised 2:1 to device-assisted CRT plus standard care (active) or standard care (control). The primary endpoint was 50% or greater reduction in PN caloric intake at 30 days, using an intention-to-treat analysis, for a comparison between randomised groups using a two tailed p-value of 0.025 to allow for a single interim analysis. Secondary outcomes were rate of PN cessation at 30 and 60 days, quality of life, and adverse events.

Results The population comprised 39 (26 active, 13 control) participants. At Day 30, 8/26 (31%) active participants achieved the primary endpoint versus no controls (p=0.035). By Day 60, 10/23 (43%) active participants had completely ceased PN versus no controls (p=0.008), with median intestinal losses reduced by 1,344 mL/day at Day 30 (p=0.005) and 1,450 mL/day at Day 60 (p=0.026 between group). Device-related adverse events were predominantly mild; one death unrelated to the device occurred.

Conclusion CRT with the Insides System demonstrated substantial therapeutic advantages in patients with T2IF from DES/ECF, with 31% of participants reducing PN calories by 50% at 30 days and >40% of participants achieving complete PN cessation by 60 days, and an acceptable safety profile.

Funding This trial was sponsored by The Insides Company Ltd.

Surgical Relevance What is already known: Patients with type 2 intestinal failure due to double enterostomy or enterocutaneous fistula depend on parenteral nutrition, which carries significant risks including central venous catheter (CVC) sepsis, venous thrombosis, and intestinal failure-associated liver disease. Chyme reinfusion therapy restores distal gut function but has only been evaluated in non-randomised cohort studies.

What is new: This first randomised controlled trial of device-assisted chyme reinfusion demonstrates that 43 per cent of participants can completely cease parenteral nutrition by 60 days, with a 70 per cent reduction in intestinal losses, high participant satisfaction and an acceptable risk profile.

Potential impact on future practice: Early initiation of device-assisted chyme reinfusion in suitable patients with double enterostomy or enterocutaneous fistula reduces parenteral nutrition dependence, avoids associated complications and costs, and facilitates rehabilitation before reconstructive surgery.

This trial was sponsored by The Insides Company Ltd. The sponsor contracted all trial operations to independent parties. Databean Inc. and GLCC Ltd served as the independent contract research organisations, with independent clinical monitoring, an independent Data Safety Monitoring Board, and independent principal investigators and clinical sites. The trial was conducted in compliance with FDA 21 CFR and ISO 14155. The sponsor had no role in participant recruitment, clinical data collection, or endpoint adjudication. The sponsor provided input in the preparation of the manuscript.

ClinicalTrials.gov (NCT04577456)

This trial was sponsored by The Insides Company Ltd. The sponsor contracted all trial operations to independent parties.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was conducted in full compliance with the ethical principles set forth in the Declaration of Helsinki (World Medical Association, Fortaleza 2013) and the requirements of Good Clinical Practice (GCP) as defined by the International Council for Harmonisation (ICH E6, R2), in accordance with applicable regulatory requirements. The rights, safety, and well-being of participants were the primary considerations and prevailed over the interests of science and society. Informed consent was obtained from all participants or their legally authorized representatives prior to enrolment, and the study protocol, along with any amendments, received approval from an independent ethics committee/institutional review board. The sponsor, investigators, and study staff fulfilled their responsibilities to ensure the reliability and integrity of the study data. The study protocol and associated documents and amendments were reviewed and approved in the USA by Advarra IRB (ref Pro00051593). In the UK the Health Research Authority for the UK and Wales (HRA and HRAW) reviewed and approved the study through the Integrated Research Application System (ref IRAS 279869). This included an ethical review by the independent Surrey Research Ethics Committee. The above mentioned IRBs rules over the trial, and full ethical approval was given for this study.

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All data produced in the present study are available upon reasonable request to the authors