Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN) : a double-blind, randomised, placebo-controlled phase 2b trial

Background IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. Methods We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035. Findings Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24.4% (SEM 7.7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0.74; 95% CI 0.59-0.94; p=0.0066). At 9 months, mean UPCR had decreased by 27.3% in 48 patients who received 16 mg/day (0.71; 0.53-0.94; p=0.0092) and 21.5% in the 51 patients who received 8 mg/day (0.76; 0.58-1.01; p=0.0290); 50 patients who received placebo had an increase in mean UPCR of 2.7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). Interpretation TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation.Peer reviewe

Routine panendoscopy in oral squamous cell cancer patients: mandatory or facultative?

Objectives!#!This study investigated benefits of routine panendoscopy in staging of oral squamous cell cancer patients.!##!Materials and methods!#!From 2013 to 2017, 194 oral squamous cell cancer patients were staged. Reports of routine flexible panendoscopy including oropharyngolaryngoscopy, bronchoscopy, and esophagogastroduodenoscopy were retrospectively analyzed for diagnoses of inflammation and second primary malignancies (carcinoma in situ or cancer) and compared to results of computed tomography. The effects of alcohol and tobacco history of 142 patients were assessed.!##!Results!#!Overall, a second primary malignancy was detected in seven patients. In four patients this discovery was only found by panendoscopy. One invasive carcinoma (esophagus) was detected as well as three carcinoma in situ. The second primary malignancies were located in the lung (3), esophagus (3), and stomach (1). In one patient index tumor therapy was modified after panendoscopy. Upper gastrointestinal inflammation was present in 73.2% of patients and 61.9% required treatment. About 91.8% of bronchoscopies and 34.5% of panendoscopies were without therapeutic consequences. Patients with higher risk from smoking were more likely to benefit from panendoscopy and to have a Helicobacter pylori infection.!##!Conclusion!#!We do not recommend routine panendoscopy for all oral squamous cell cancer patients. Esophagogastroduodenoscopy benefitted smoking patients primarily concerning the secondary diagnosis of inflammation of the upper digestive tract. Selective bronchoscopy, esophagogastroduodenoscopy, and oropharyngolaryngoscopy should be performed if clinical examination or medical history indicates risks for additional malignancies of the upper aerodigestive tract.!##!Clinical relevance!#!Routine panendoscopy is not recommended in all, especially not in low-risk oral cancer patients like non-smokers and non-drinkers

Bronchoscopic Coil Treatment for Patients with Severe Emphysema: A Meta-Analysis

Background: Bronchoscopic coil treatment has been shown to improve pulmonary function, exercise capacity, and quality of life in patients with severe emphysema. Objectives: To perform a meta-analysis of the results of four independent European clinical trials investigating this coil therapy for emphysema. Methods: Data on all patients included in the four European clinical trials were analyzed for efficacy and safety outcomes. Results: A total of 2,536 coils were placed during 259 procedures in 140 patients. A total of 37 chronic obstructive pulmonary disease exacerbations and 27 pneumonias were recorded as serious adverse events up to 1 year after treatment. The pneumothorax rate was 6.4%. Both 6 and 12 months after treatment, significant (all p <0.001) improvements were observed for: forced expiratory volume in 1 s [+0.08 liters (+/- 0.19) and +0.08 liters (+/- 0.21)], residual volume [RV; -510 ml (+/- 850) and -430 ml (+/- 720)], 6-min walking distance [6MWD; +44.1 m (+/- 69.8) and +38.1 m (+/- 71.9)], and St. George's Respiratory Questionnaire score [SGRQ; -9.5 points (+/- 14.3) and -7.7 points (+/- 14.2)]. No differences in any outcome measures were observed between heterogeneous and homogeneous emphysema patients. Only a high baseline RV was found to be an independent predictor of successful treatment. Conclusions: Bronchoscopic coil treatment improves pulmonary function, 6MWD, and quality of life in patients with severe emphysema up to 1 year after treatment, independent of the distribution of the disease. (C) 2015 S. Karger AG, Base

Endobronchial Coils Versus Lung Volume Reduction Surgery or Medical Therapy for Treatment of Advanced Homogenous Emphysema

International audienc

Endobronchial Coils Versus Lung Volume Reduction Surgery or Medical Therapy for Treatment of Advanced Homogenous Emphysema

Rationale: Bronchoscopic lung volume reduction utilizing shape-memory nitinol endobronchial coils (EBC) may be safer and more effective in severely hyperinflated homogeneous emphysema compared to medical therapy or lung volume reduction surgery (LVRS). Methods: The effect of bilateral EBC in patients with homogeneous emphysema on spirometry, lung volumes and survival was compared to patients with homogeneous emphysema randomized in the National Emphysema Treatment Trial (NETT) to LVRS or medical therapy. NETT participants were selected to match EBC participants in age, baseline spirometry, and gender. Outcomes were compared from baseline, at 6 and 12 months. Results: There were no significant baseline differences in gender in the EBC, NETT-LVRS or medical treatment patients. At baseline no differences existed between EBC and NETT-LVRS patients in forced expiratory volume in 1 second ( FEV1) or total lung capacity (TLC) %-predicted; residual volume (RV) and diffusing capacity of the lung for carbon monoxide (DLco) %-predicted were higher in the EBC group compared to NETT-LVRS (p < 0.001). Compared to the medical treatment group, EBC produced greater improvements in FEV1 and RV but not TLC at 6 months. FEV1 and RV in the EBC group remained significantly improved at 12-months compared to the medical treatment group. While all 3 therapies improved quality of life, survival at 12 months with EBC or medical therapy was greater than NETT-LVRS. Conclusion: EBC may be a potential therapeutic option in patients with severe homogeneous emphysema and hyperinflation who are already receiving optimal medical treatment