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Introduction Proximal intestinal mucosal ablation (PIMA) is an endoscopic procedure that aims to replicate the glycaemic benefits of gastric bypass surgery by ablating up to 60 cm of small intestinal mucosa in patients with type 2 diabetes (T2D). PIMA is completed with a through-the-scope, radiofrequency vapor ablation (RFVA) mesh-tip catheter. We hypothesised that ablation of a longer segment of small bowel could lead to an improved and more durable glycaemic response compared to duodenal mucosal ablation, without compromising safety. Accordingly, we report the first-in-human evaluation of PIMA, which aimed to assess its safety, tolerability, feasibility, and early efficacy.Methods A prospective, single centre first-in-human study evaluating PIMA using RFVA for the treatment of inadequately controlled T2D (glycated haemoglobin [HbA1c] 7.5-10.0%) despite ≥1 oral glucose lowering agent (GLA; NCT05887635). After screening, patients underwent a 4-week run-in to ensure stable glycemia before undergoing PIMA between Sep-2024 to May-2025, alongside standard lifestyle advice for T2D. PIMA was performed via an adult colonoscope (Olympus HQ190L) with the RFVA catheter under general anaesthesia. RFVA was delivered at a dose of 250-275J with double application to the intestinal mucosa. Patients were discharged within 24 hours on a modified day for 14-days. Technical success was defined as ≥20 cm of ablated post-ampullary mucosa. The primary outcomes were safety (serious adverse events), tolerability (visual analogue score [VAS] for pain post-procedure), feasibility (procedure time and ablation length), and reduction in HbA1c at 3- and 6-months. Secondary outcomes included metabolic, anthropometric, and hepatic measures.Results In total, 13 patients (average age 52 years [IQR 45-61], 38.5% female) underwent PIMA. The average duration of T2D was 6 years (IQR 5-9), baseline HbA1c was 9.3% (SD 0.7), BMI was 31.4 kg/m2 (SD 2.5) and average number of GLAs was 1 (IQR 1-2). PIMA was successful in all patients with an average treatment length of 54 cm (IQR 44-60) and 40.8 (SD 10.7) ablations. Six patients were treated at 250J and seven 275J. The average procedure time was 62.2 minutes (SD 14.4) and catheter time 51.3 minutes (SD 19.2). PIMA was well-tolerated with a maximum median VAS score of 1 (IQR 0-2) on day 2. All patients reached the 6-month follow-up with no adverse events related to the procedure or episodes of hypoglycaemia. Follow-up enteroscopy and biopsy was normal in all cases. Median reduction in HbA1c at 3- and 6-months was 2.5% (IQR 1.4-2.9; p<0.0001) and 2.2% (IQR 1.0-2.5; p=0.0001), respectively, without a significant change in BMI (-0.6 [SD 1.3] 3-months, -1.0 [SD 1.9] 6-months).Conclusions PIMA demonstrated an acceptable safety and tolerability profile with evidence of feasibility and clinically meaningful reductions in glycated haemoglobin.