Publications

BASALIT trial: double-blind placebo-controlled allergen immunotherapy with rBet v 1-FV in birch-related soya allergy.

Abstract (Expand)

BACKGROUND: Conflicting results exist on the effect of allergen immunotherapy (AIT) on pollen-related food allergy. We aimed to investigate the efficacy of one-year AIT with the folding variant (FV) … of recombinant (r) Bet v 1 on birch-related soya allergy. METHODS: Of 138 subjects with Bet v 1 sensitization, 82 were positive at double-blind placebo-controlled food challenge (DBPCFC) with soya. A total of 56 of 82 were randomized in the ratio of 2:1 (active: placebo). Per-protocol population (PPP) had received >/=150 mug of allergen or placebo preparation. OUTCOME MEASURES: lowest observed adverse effect levels (LOAEL), postinterventional occurrence of objective signs (objS) at any dose level, sIgE/IgG4 against Bet v 1 and Gly m 4. Between-group changes were investigated (ancova, Mann-Whitney U-test, Fisher exact test). RESULTS: Baseline characteristics including LOAELs were comparable in both groups with objS and subjS occurring in 82% and 95% of active (n = 38) vs 78% and 83% of placebo group (n = 18). After AIT, objS occurred in 24% and 47%, respectively. LOAEL group differences showed a beneficial tendency (P = 0.081) for LOAEL(objective) in PPP (30 active, 15 placebo). sIgG4 raised only in active group (Bet v 1: P = 0.054, Gly m 4: P = 0.037), and no relevant changes occurred for sIgE. Only 56% of the intended sample size was recruited. CONCLUSION: For the first time, we present data on the effect of rBet v 1-FV on birch-related soya allergy. rBet v 1-FV AIT induced significant immunogenic effects. Clinical assessment showed a tendency in favour of the active group but did not reach statistical significance.

Authors: R. Treudler, A. Franke, A. Schmiedeknecht, B. Ballmer-Weber, M. Worm, T. Werfel, U. Jappe, T. Biedermann, J. Schmitt, R. Brehler, A. Kleinheinz, J. Kleine-Tebbe, H. Bruning, F. Rueff, J. Ring, J. Saloga, K. Schakel, T. Holzhauser, S. Vieths, J. C. Simon

Date Published: 21st Dec 2016

Publication Type: Journal

A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B.

Abstract (Expand)

BACKGROUND & AIMS: Nucleos(t)ide analogues (NUCs) are the standard and mostly lifelong treatment for chronic HBeAg-negative hepatitis B, as functional cure (loss of HBsAg) is rarely achieved. … Discontinuation of NUC treatment may lead to functional cure; however, to date, the evidence for this has been based on small or non-randomized clinical trials. The STOP-NUC trial was designed with the aim of increasing the HBsAg loss rate using a NUC treatment interruption approach. METHODS: In this multicenter, randomized-controlled trial, 166 HBeAg-negative patients with chronic hepatitis B on continuous long-term NUC treatment, with HBV DNA <172 IU/ml (1,000 copies/ml) for >/=4 years, were randomized to either stop (Arm A) or continue NUC treatment (Arm B) for a 96-week observation period. In total, 158 patients were available for final analysis, 79 per arm. The primary endpoint was sustained HBsAg loss up to week 96. RESULTS: Our study met its primary objective by demonstrating HBsAg loss in eight patients (10.1%, 95% CI 4.8%-19.5%) in Arm A and in no patient in Arm B (p = 0.006). Among patients with baseline HBsAg levels <1,000 IU/ml, seven (28%) achieved HBsAg loss. In Arm A, re-therapy was initiated in 11 (13.9%) patients, whereas 32 (40.5%) patients achieved sustained remission. A decrease of HBsAg >1 log IU/ml was observed in 16 patients (20.3%) in Arm A and in one patient (1.3%) in Arm B. No serious adverse events related to treatment cessation occurred. CONCLUSIONS: Cessation of NUC treatment was associated with a significantly higher rate of HBsAg loss than continued NUC treatment, which was largely restricted to patients with end of treatment HBsAg levels <1,000 IU/ml. IMPACT AND IMPLICATIONS: As HBeAg-negative patients with chronic hepatitis B on nucleos(t)ide analogues (NUCs) rarely achieve functional cure, treatment is almost always lifelong. The STOP-NUC trial was conducted to investigate whether discontinuing long-term NUC treatment can increase the cure rate. We found that some patients achieved functional cure after stopping NUCs, which was especially pronounced in patients with HBsAg levels <1,000 at the end of NUC treatment, and that many did not need to resume therapy. The results of the Stop-NUC trial provide evidence for the concept of stopping NUC treatment as a therapeutic option that can induce functional cure.

Authors: F. van Bommel, K. Stein, R. Heyne, J. Petersen, P. Buggisch, C. Berg, S. Zeuzem, A. Stallmach, M. Sprinzl, E. Schott, A. Pathil-Warth, U. von Arnim, V. Keitel, J. Lohmeyer, K. G. Simon, C. Trautwein, A. Trein, D. Huppe, M. Cornberg, F. Lammert, P. Ingiliz, R. Zachoval, H. Hinrichsen, A. Zipprich, H. Klinker, J. Schulze Zur Wiesch, A. Schmiedeknecht, O. Brosteanu, T. Berg

Date Published: 18th Apr 2023

Publication Type: Journal

Nasal high-flow versus noninvasive ventilation in patients with chronic hypercapnic COPD.

Abstract (Expand)

BACKGROUND: Despite the encouraging results of noninvasive ventilation (NIV) in chronic hypercapnic COPD patients, it is also evident that some patients do not tolerate NIV or do not benefit from it. … We conducted a study in which COPD patients with stable, chronic hypercapnia were treated with NIV and nasal high-flow (NHF) to compare effectiveness. METHODS: In a multi-centered, randomized, controlled, cross-over design, patients received 6 weeks of NHF ventilation followed by 6 weeks of NIV ventilation or vice-versa (TIBICO) between 2011 and 2016. COPD patients with stable daytime hypercapnia (pCO(2)>/=50 mmHg) were recruited from 13 German centers. The primary endpoint was pCO(2) changes from baseline blood gas, lung function, quality of life (QoL), the 6 min walking test, and duration of device use were secondary endpoints. RESULTS: A total of 102 patients (mean+/-SD) age 65.3+/-9.3 years, 61% females, body mass index 23.1+/-4.8 kg/m(2), 90% GOLD D, pCO(2) 56.5+/-5.4 mmHg were randomized. PCO(2) levels decreased by 4.7% (n=94; full analysis set; 95% CI 1.8-7.5, P=0.002) using NHF and 7.1% (95% CI 4.1-10.1, P<0.001) from baseline using NIV (indistinguishable to intention-to-treat analysis). The difference of pCO(2) changes between the two devices was -1.4 mmHg (95% CI -3.1-0.4, P=0.12). Both devices had positive impact on blood gases and respiratory scores (St. George's Respiratory Questionnaire, Severe Respiratory Insufficiency Questionnaire). CONCLUSIONS: NHF may constitute an alternative to NIV in COPD patients with stable chronic hypercapnia, eg, those not tolerating or rejecting NIV with respect to pCO(2) reduction and improvement in QoL.

Authors: J. Braunlich, D. Dellweg, A. Bastian, S. Budweiser, W. Randerath, D. Triche, M. Bachmann, C. Kahler, A. H. Bayarassou, I. Mader, J. Geiseler, N. Kohler, D. Petroff, H. Wirtz

Date Published: 17th Jul 2019

Publication Type: Journal

Antibodies in the diagnosis of coeliac disease: a biopsy-controlled, international, multicentre study of 376 children with coeliac disease and 695 controls.

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Diagnosis of coeliac disease (CD) relies on a combination of clinical, genetic, serological and duodenal morphological findings. The ESPGHAN suggested that biopsy may not be necessary in all cases. New … guidelines include omission of biopsy if the concentration of CD-specific antibodies exceeds 10 times the upper limit of normal (10 ULN) and other criteria are met. We analysed the 10 ULN criterion and investigated multiple antibody-assays. Serum was collected from 1071 children with duodenal biopsy (376 CD patients, 695 disease-controls). IgA-antibodies to tissue transglutaminase (IgA-aTTG), IgG-antibodies to deamidated gliadin peptides (IgG-aDGL) and IgA-endomysium antibodies (IgA-EMA) were measured centrally. We considered 3 outcomes for antibody test procedures utilizing IgA-aTTG and/or IgG-aDGL: positive (>/=10 ULN, recommend gluten-free diet), negative (<1 ULN, no gluten-free diet) or unclear (perform biopsy). Positive (PPV) and negative (NPV) predictive values were based on clear test results. We required that they and their lower confidence bounds (LCB) be simultaneously very high (LCB >90% and PPV/NPV >95%). These stringent conditions were met for appropriate antibody-procedures over a prevalence range of 9-57%. By combining IgG-aDGL with IgA-aTTG, one could do without assaying total IgA. The PPV of IgG-aDGL was estimated to be extremely high, although more studies are necessary to narrow down the LCB. The proportion of patients requiring a biopsy was <11%. The procedures were either equivalent or even better in children <2 years compared to older children. All 310 of the IgA-aTTG positive children were also IgA-EMA positive. Antibody-assays could render biopsies unnecessary in most children, if experienced paediatric gastroenterologists evaluate the case. This suggestion only applies to the kits used here and should be verified for other available assays. Confirming IgA-aTTG positivity (>/=10 ULN) by EMA-testing is unnecessary if performed on the same blood sample. Prospective studies are needed.

Authors: J. Wolf, D. Hasenclever, D. Petroff, T. Richter, H. H. Uhlig, M. W. Laass, A. Hauer, M. Stern, X. Bossuyt, J. de Laffolie, G. Flemming, D. Villalta, W. Schlumberger, T. Mothes

Date Published: 17th May 2014

Publication Type: Journal

Individualized positive end-expiratory pressure in obese patients during general anaesthesia: a randomized controlled clinical trial using electrical impedance tomography.

Abstract (Expand)

BACKGROUND: General anaesthesia leads to atelectasis, reduced end-expiratory lung volume (EELV), and diminished arterial oxygenation in obese patients. We hypothesized that a combination of a recruitment … manoeuvre (RM) and individualized positive end-expiratory pressure (PEEP) can avoid these effects. METHODS: Patients with a BMI >/=35 kg m -2 undergoing elective laparoscopic surgery were randomly allocated to mechanical ventilation with a tidal volume of 8 ml kg -1 predicted body weight and (i) an RM followed by individualized PEEP titrated using electrical impedance tomography (PEEP IND ) or (ii) no RM and PEEP of 5 cm H 2 O (PEEP 5 ). Gas exchange, regional ventilation distribution, and EELV (multiple breath nitrogen washout method) were determined before, during, and after anaesthesia. The primary end point was the ratio of arterial partial pressure of oxygen to inspiratory oxygen fraction ( P aO 2 / F iO 2 ). RESULTS: For PEEP IND ( n =25) and PEEP 5 ( n =25) arms together, P aO 2 / F iO 2 and EELV decreased by 15 kPa [95% confidence interval (CI) 11-20 kPa, P <0.001] and 1.2 litres (95% CI 0.9-1.6 litres, P <0.001), respectively, after intubation. Mean ( sd ) PEEP IND was 18.5 (5.6) cm H 2 O. In the PEEP IND arm, P aO 2 / F iO 2 before extubation was 23 kPa higher (95% CI 16-29 kPa; P <0.001), EELV was 1.8 litres larger (95% CI 1.5-2.2 litres; P <0.001), driving pressure was 6.7 cm H 2 O lower (95% CI 5.4-7.9 cm H 2 O; P <0.001), and regional ventilation was more equally distributed than for PEEP 5 . After extubation, however, these differences between the arms vanished. CONCLUSIONS: In obese patients, an RM and higher PEEP IND restored EELV, regional ventilation distribution, and oxygenation during anaesthesia, but these differences did not persist after extubation. Therefore, lung protection strategies should include the postoperative period. CLINICAL TRIAL REGISTRATION: German clinical trials register DRKS00004199, www.who.int/ictrp/network/drks2/en/ .

Authors: C. Nestler, P. Simon, D. Petroff, S. Hammermuller, D. Kamrath, S. Wolf, A. Dietrich, L. M. Camilo, A. Beda, A. R. Carvalho, A. Giannella-Neto, A. W. Reske, H. Wrigge

Date Published: 1st Dec 2017

Publication Type: Journal

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study).

Abstract (Expand)

BACKGROUND & AIMS: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic … liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 mug/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. RESULTS: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. GOV NUMBER: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Authors: C. Engelmann, A. Herber, A. Franke, T. Bruns, P. Reuken, I. Schiefke, A. Zipprich, S. Zeuzem, T. Goeser, A. Canbay, C. Berg, J. Trebicka, F. E. Uschner, J. Chang, T. Mueller, N. Aehling, M. Schmelzle, K. Splith, F. Lammert, C. M. Lange, C. Sarrazin, C. Trautwein, M. Manns, D. Haussinger, J. Pfeiffenberger, P. R. Galle, A. Schmiedeknecht, T. Berg

Date Published: 9th Aug 2021

Publication Type: Journal

The BASALIT multicenter trial: Gly m 4 quantification for consistency control of challenge meal batches and toward Gly m 4 threshold data.

Abstract (Expand)

SCOPE: The BASALIT clinical trial (EudraCT 2009-011737-27) investigated efficacy of birch allergen immunotherapy on lowest observed adverse effect levels after soy food challenge in patients with … birch-associated and Gly m 4 allergen mediated soy allergy. Thus, consistently stable Gly m 4 levels were required in standardized challenge meals. METHODS AND RESULTS: Soy meal included soy protein isolate (SPI, 88% total protein). A Gly m 4 specific ELISA was developed and validated. Six SPIs and 24 meal batches were analyzed for Gly m 4. (Repeated-measures) analyses of variance were done to identify potential changes between batches and time intervals. Gly m 4 was below the ELISA detection limit (2 ng/mL) in placebo batches. With <20% mean coefficient of variation, Gly m 4 levels were consistent in 24 soy meal batches and within individual 12-wk shelf-life. CONCLUSION: The novel Gly m 4 specific ELISA proved consistency of challenge meal batches over a 56-month study period. With an average of 178 mug/g Gly m 4 in SPI, Gly m 4 lowest observed adverse effect level can be calculated once clinical lowest observed adverse effect level data based on SPI are available. Hence, sensitivity of patients can be correlated to the relevant allergen content instead of total protein of the allergenic source.

Authors: T. Holzhauser, A. Franke, R. Treudler, A. Schmiedeknecht, S. Randow, W. M. Becker, J. Lidholm, S. Vieths, J. C. Simon

Date Published: 18th Oct 2016

Publication Type: Journal

Peptide epitopes as biomarkers of soya sensitization in rBet v 1 immunotherapy of birch-related soya allergy.

Abstract (Expand)

BACKGROUND: There are no diagnostic and/or prognostic markers of the treatment outcome in patients receiving allergen immunotherapy (AIT). Although numerous allergen epitopes are known, their value in … this context has not been investigated. This paper deals with re-evaluation of sera from patients who underwent AIT against rBet v 1 for treatment of their soya allergy (BASALIT trial). OBJECTIVE: To evaluate the diagnostic and/or prognostic potential of allergen epitopes recognition by antibodies from patients with birch-related soya allergy before and after rBet v 1-immunotherapy. METHODS: PR-10 epitope-binding profiles from 34 patients were identified in silico using a statistical peptide phage display at start and at end of AIT. IgE- and IgG-binding to these peptide epitopes was measured in peptide microarrays. Clinical relevance of epitopes was evaluated by comparing these measurements to a number of treatment outcome measures recorded during double-blind placebo-controlled food challenge at start and end of AIT. RESULTS: We showed that IgG- and IgE-recognition of peptide epitopes after AIT were surrogate markers of 5 out of 12 analysed treatment outcome measures using this patient cohort. Seven epitopes were identified from multiple PR-10 allergen sequences. Twenty-six peptide epitopes were used for IgG and IgE measurements. IgE-binding to one of the epitopes was associated with stronger intensity of oral tingling/itching after ingesting soya at start of AIT. IgG recognizing two other epitopes at start of AIT could predict decreased Cor a 1-specific IgE concentration (p = .043) and decreased lip swelling intensity (p = .016) after AIT. Tolerance to increasing amounts of soy at food challenge correlated with IgG-binding to another epitope at start of AIT (p = .046). CONCLUSION: IgG- and IgE-binding to peptide epitopes in PR-10 is a potential indicator of the outcome and clinical course of AIT of soya-sensitized patients with rBet v 1.

Authors: L. R. Caballero, R. Treudler, N. Delaroque, J. C. Simon, K. Kern, M. Szardenings

Date Published: 15th Sep 2022

Publication Type: Journal

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