Introduction

There are currently no studies comparing vonoprazan-dual, vonoprazan-triple therapies and classic bismuth quadruple therapy.

Aims & Methods

We aimed to compare efficacy of vonoprazan-dual or triple therapies and bismuth-quadruple therapy for treatment-naive Helicobacter pylori (HP) infection in Southern China, where primary resistance rates of clarithromycin and levofloxacin are >30%.
Between March 2022 and August 2023, treatment-naïve HP-infected adults were randomly assigned to receive one of the three 14-day regimens (1:1:1 ratio): vonoprazan-dual (VA-dual; vonoprazan 20mg twice daily and amoxicillin 1g thrice daily), vonoprazan-triple (VAC-triple; vonoprazan 20mg/amoxicillin 1g/clarithromycin 500mg twice daily), or bismuth-quadruple therapy containing bismuth, esomeprazole, tetracycline and metronidazole. Primary outcome was noninferiority in HP eradication, evaluated by UBT 4-6 weeks post-treatment by intention-to-treat (ITT) (based on all recruited subjects who took at least one dose of treatment regimen, and those lost to follow-up were considered as treatment failure cases), modified intention-to-treat (mITT) (based on patients who took at least one dose of the treatment and completed follow-up) and per-protocol (PP) analysis (based on subjects who completed 14-day treatment and rechecked UBT). Bonferroni-adjusted p-value of <0.017 was used to determine statistical significance. Primary outcome was noninferiority in HP eradication, evaluated by UBT 4-6 weeks post-treatment by intention-to-treat (ITT) and per-protocol (PP) analysis (based on subjects who completed 14-day treatment and rechecked UBT). Comparative non-inferiority between bismuth-quadruple and VA-dual or VAC-triple was assessed by one-sided μ test and derivation of a two-sided 95% confidence interval (CI), with noninferiority being determined by a lower 95% CI end more than –10% with a Bonferroni-adjusted p-value of <0.017. A two-sided p-value of 0.05 was used to define statistical significance for other analyses.

Results

298 subjects (mean age:35.7±8.4 years; male:134 [45.0%]; body mass index:23.2±3.5 kg/m²; VC-dual:100, VAC-triple:98, bismuth-quadruple:100) were enrolled, and 292 (98.0%) had UBT rechecked. ITT analysis showed both VA-dual (eradication rate of 96.0%) and VAC-triple therapies (95.9%) were non-inferior to bismuth-quadruple therapy (92.0%) (difference:4.0%, 95% CI:-2.9% to 11.5%, p<0.001; and 3.9%, 95% CI:-3.1% to 11.5%, p<0.001, respectively). mITT analysis also showed non-inferiority of VA-dual and VAC-triple therapies to bismuth-quadruple therapy (97.0% and 96.9% vs 95.8%, with difference:1.1% and 1.1%, p=0.002 and 0.002, respectively). Similar observation was noted for PP analysis (96.7% and 96.7% vs 97.4%, with difference:-0.7% and -0.7%, p=0.009 and 0.010, respectively) (Table 1). The frequency of adverse events was 39.0%, 56.1% and 71.0% in VA-dual, VAC-triple and bismuth-quadruple therapies, respectively.

Table 1. Helicobacter pylori eradication rates of vonoprazan-dual, vonoprazan-triple and bismuth-quadruple therapies

Conclusion

VA-dual and VA-triple therapies were non-inferior to bismuth-quadruple therapy in Southern China. Given the lower adverse effects and fewer antibiotic use, VA-dual therapy is the preferred first-line treatment for HP infection.

Disclosure

This study was supported by the National Natural Science Foundation of China (Grant No. 81903581), the Shenzhen Science and Technology Program (Grant Nos. JCYJ20190807150005699 and RCBS20200714115000009), the Shenzhen Key Medical Discipline Construction Fund (Grant No. SZXK059), the Shenzhen Key Laboratory of Prevention and Treatment of Severe Infections (Grant No. ZDSYS20200811142804014), and the Health Commission Grant of Guangdong Province, China (ref. no. B2021239).

Introduction

Complex perianal fistulas represent one of the most challenging manifestations of Crohn’s disease. Combined surgical and medical therapy with biologic drugs represents today the first-line treatment option, but its efficacy does not exceed 60% in terms of healing. Recently, new therapeutic approaches, such as autologous microfragmented adipose tissue (M-Fat) injection, have shown promising results. Indeed, a recent non-profit prospective pilot study on 15 patients has demonstrated that the local injection of M-Fat is a safe and promising “rescue therapy” for patients with multiresistant complex fistulizing Crohn’s disease (PCD), with a 66.7% rate of combined remission in such difficult patients. It has to be highlighted that the M-Fat injection is minimally invasive, with less risk of sphincteric damage and can be carried out in day-surgery setting.

Aims & Methods

The primary aim of this multicentre double-blind randomized controlled trial (ATTIC) is to evaluate the efficacy of the infiltration of M-Fat in the healing of perianal complex fistulas not-responding to treatment with biologics. Consecutive patients referring to the 6 investigation Centers for surgical treatment of persistent complex fistulizing PCD refractory to biosurgical approach were assessed for eligibility. After baseline pelvic magnetic resonance imaging, those included were submitted to surgical drainage with “cone-like” fistulectomy, and then randomized to receive a 15 to 20 cc local injection, at the internal orifice level and along fistula tracts, of M-Fat obtained by a lipoaspiration and processed with an enzyme-free technology (treatment group), or a suture placement and injection of 15 cc of saline solution at the internal orifice (control group). Clinical follow-up were conducted at 2, 4, 8, 12, and 24 weeks; at 24 weeks after surgery, pelvic magnetic resonance was obtained. Success was defined as “combined remission”, combination of clinical (absence of drainage upon gentle finger compression) and radiological healing (absence of residual collections > 3 mm). Clinical remission was defined as clinical healing of all external openings not confirmed at radiological assessment.

Results

An overall 92 patients were screened, and 66 (33 per group) completed the 24-week follow-up. A statistically significant difference in favour of the treatment group in terms of combined remission emerged at the primary endpoint at 24-week follow-up (control group, 18.18%; treatment group: 57.58%; p = 0.0020). No significant differences in clinical outcome measures were encountered at any of the other follow-up points. No significant differences emerged between the groups in terms of recurrence rate, complication rate, and number of adverse events. Clinical remission was 63.64% in the treatment group compared to 51.52% in the control group with no statistically significant difference (p > 0.05).

Conclusion

This multicentre double-blind randomized controlled trial demonstrates that the intraoperative injection of M-Fat, associated with surgical complete drainage of perianal sepsis, is safe, effective, and reproducible in healing complex multirefractory perianal Crohn's disease, while improving the quality of life and significantly reducing the risk of definitive oostomy.

Introduction

In Parts A and B of the 3-part phase 3 LIBERTY EoE TREET study (NCT03633617), dupilumab 300 mg weekly (DPL qw) vs placebo (PBO) demonstrated significant efficacy and acceptable safety up to 24 weeks in adults and adolescents with eosinophilic esophagitis (EoE). For patients who completed Parts A and B, Part C was an extended active treatment period for 28 weeks with patients receiving treatment up to 52 weeks. We previously reported continued improvements in all aspects of disease up to 52 weeks in DPL patients who completed Part A/C, and that PBO patients from Part A who received DPL in Part C showed similar efficacy. Here we present results from patients who completed Part B and continued to Part C, which assessed efficacy and safety of DPL up to 52 weeks in a larger number of patients.

Aims & Methods

Of 80 DPL qw patients in Part B, 74 continued DPL qw in Part C (DPL/DPL). Of 79 PBO patients in Part B, 37 received DPL qw in Part C (PBO/DPL). Part B co-primary endpoints were proportion of patients achieving peak esophageal intraepithelial eosinophil (eos) count ≤6 eos/high power field (hpf) and absolute change from Part B baseline (BL) in Dysphagia Symptom Score (DSQ) score at Week 24. Secondary endpoints are listed in the Table. In Part C, all endpoints were assessed at Week 52 as secondary endpoints. Safety was also assessed.

Table. Summary of co-primary and secondary endpoints at Weeks 24 (Part B) and 52 (Part C) of the 3-part phase 3 LIBERTY EoE TREET study.

Results

Part B BL characteristics were similar across groups. At Week 52 of Part C, 84.6% of patients in the DPL/DPL and 67.6% of patients in the PBO/DPL groups achieved peak eos count of ≤6 eos/hpf and mean (SD) absolute change from Part B BL in DSQ score was −30.26 (15.39) for DPL/DPL and −27.25 (11.46) for PBO/DPL patients. At Week 52, 100% of patients in the DPL/DPL and 78.4% PBO/DPL groups achieved peak eos count of <15 eos/hpf. Compared to Part B BL, peak eos count, EREFS, HSS grade and stage scores were reduced, and EDP and T2 normalized enrichment scores were suppressed in the DPL/DPL and PBO/DPL groups at Week 52 (Table). Dupilumab demonstrated an acceptable safety profile in Part C; the most common (occurring ≥10%) treatment-emergent adverse events in the DPL/DPL and PBO/DPL groups were injection-site reactions (13.5% and 10.8%), COVID-19 (9.5% and 10.8%), and nasopharyngitis (4.1% and 10.8%).

Conclusion

As observed in Part A/C, dupilumab qw demonstrated persistent improvements in clinical, symptomatic, histologic, endoscopic, and molecular features of EoE up to 52 weeks and Overall safety was consistent with the known dupilumab safety profile. PBO patients from Part B who received dupilumab in Part C showed similar efficacy to dupilumab qw patients of Part B.

Disclosure

Dellon ES: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nextstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio – consultant; Adare/Ellodi, Allakos, Arena, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda – research funding; Allakos, Holoclara, Invea – educational grant.
Rothenberg ME: Allakos, AstraZeneca, BMS, Celldex, ClostraBio, Ellodi Pharmaceuticals, GSK, Nextstone One, PulmOne, Regeneron Pharmaceuticals Inc., Revolo, Sanofi, Santa Ana Bio, Serpin Pharma, Spoon Guru ‒ consultant; Celldex, ClostraBio, Nextstone One, PulmOne, Santa Ana Bio, Serpin Pharma, Spoon Guru ‒ equity interest; Mapi Research Trust ‒ royalties from PEESSv2; Teva Pharmaceuticals ‒ royalties from reslizumab; UpToDate ‒ royalties; inventor of patents owned by Cincinnati Children’s Hospital.
Collins MH: Alimentiv, Allakos, Arena, AstraZeneca, BMS, Calypso, EsoCap, GSK, Regeneron Pharmaceuticals, Inc., Shire – consultant.
Hirano I: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eli Lilly, EsoCap, Gossamer Bio, GSK, Nexstone Immunology, Parexel/Calyx, Phathom, Receptos/BMS, Regeneron Pharmaceuticals Inc., Sanofi, Shire/Takeda – consultant; Adare/Ellodi, Allakos, Receptos/BMS, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding.
Chehade M: Adare/Ellodi, Allakos, AstraZeneca, BMS, Phathom; Recludix, Regeneron Pharmaceuticals Inc., Sanofi, Shire/Takeda – consultant; Adare/Ellodi, Allakos, AstraZeneca, Danone, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding.