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4 Publications visible to you, out of a total of 4
Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study.

Abstract (Expand)

BACKGROUND: The human cytokine erythropoietin conveys neuroprotection in animal models but has shown ambiguous results in phase 2 clinical trials in patients with optic neuritis. We assessed the safety … and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome in a multicentre, prospective, randomised clinical trial. METHODS: This randomised, placebo-controlled, double-blind phase 3 trial, conducted at 12 tertiary referral centres in Germany, included participants aged 18-50 years, within 10 days of onset of unilateral optic neuritis, with visual acuity of 0.5 or less, and without a previous diagnosis of multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33 000 IU erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg per day). Block randomisation was performed by the trial statistician using an SAS code that generated randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked to treatment assignment, except the trial pharmacist. The first primary outcome was atrophy of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic coherence tomography (OCT) as the difference in pRNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast letter acuity at week 26, measured as the 2.5% Sloan chart score of the affected eye. Analysis was performed in the full analysis set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. This trial is registered at ClinicalTrials.gov, NCT01962571. FINDINGS: 108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017, of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were excluded from the primary analysis due to not receiving the allocated medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding a full analysis set of 52 patients in the erythropoietin group and 51 in the placebo group. Mean pRNFL atrophy was 15.93 mum (SD 14.91) in the erythropoietin group and 14.65 mum (15.60) in the placebo group (adjusted mean treatment difference 1.02 mum; 95% CI -5.51 to 7.55; p=0.76). Mean low contrast letter acuity scores were 49.60 (21.31) in the erythropoietin group and 49.06 (21.93) in the placebo group (adjusted mean treatment difference -4.03; -13.06 to 5.01). Adverse events occurred in 43 (81%) participants in the erythropoietin group and in 42 (81%) in the placebo group. The most common adverse event was headache, occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients in the placebo group. Serious adverse events occurred in eight (15%) participants in the erythropoietin and in four (8%) in the placebo group. One patient (2%) in the erythropoietin group developed a venous sinus thrombosis, which was treated with anticoagulants and resolved without sequelae. INTERPRETATION: Erythropoietin as an adjunct to corticosteroids conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Future research could focus on modified erythropoietin administration, assess its efficacy independent of corticosteroids, and investigate whether it affects the conversion of optic neuritis to multiple sclerosis. FUNDING: German Federal Ministry of Education and Research (BMBF).

Authors: W. A. Lagreze, S. Kuchlin, G. Ihorst, B. Grotejohann, F. Beisse, M. Volkmann, S. P. Heinrich, P. Albrecht, J. Ungewiss, M. Worner, M. J. Hug, S. Wolf, R. Diem

Date Published: 21st Nov 2021

Publication Type: Journal

Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 x 2, Phase II Trial.

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PURPOSE: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A … randomized, phase II trial with a 2 x 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all-trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m(2) intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of alpha = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.

Authors: M. Lubbert, O. Grishina, C. Schmoor, R. F. Schlenk, E. Jost, M. Crysandt, M. Heuser, F. Thol, H. R. Salih, M. M. Schittenhelm, U. Germing, A. Kuendgen, K. S. Gotze, H. W. Lindemann, C. Muller-Tidow, G. Heil, S. Scholl, G. Bug, C. Schwaenen, A. Giagounidis, A. Neubauer, J. Krauter, W. Brugger, M. De Wit, R. Wasch, H. Becker, A. M. May, J. Duyster, K. Dohner, A. Ganser, B. Hackanson, H. Dohner

Date Published: 20th Jan 2020

Publication Type: Journal

Rejection Prophylaxis in Corneal Transplant.

Abstract (Expand)

BACKGROUND: Graft rejection. Twenty to thirty percent of patients with corneal transplants experience at least one rejection episode in the first 5 years after transplantation. Prophylaxis through … matching for human leukocyte antigens (HLA) is controversial. We herein report the results of the Functional ANtigen matChing in keratoplastY (FANCY) trial. METHODS: FANCY was a randomized, double-blind, multicenter clinical trial. The primary objective was to evaluate superiority of HLA matching versus random graft assignment. The primary endpoint was rejection-free graft survival. We included both normal-risk and high-risk indications. The study is registered with ClinicalTrials. gov (NCT00810472). RESULTS: 721 patients were included, 639 patients were randomized. 474 patients underwent keratoplasty within the study; 165 patients received grafts outside the trial. One patient died and one patient was lost to follow up. We observed 33 graft rejections in the HLA matching arm (n = 224). The corresponding estimated cumulative incidence rate of immune reactions after two years was 15.7%. We observed 40 rejections in the control arm (n = 249). After two years this yields an estimated cumulative incidence rate of 17%. CONCLUSION: In our heterogenous study group, HLA matching did not show a significant advantage compared to random graft assignment. The rejection rate in our sample was lower than expected. Therefore no definite conclusions can be drawn as to whether HLA matching is beneficial in corneal transplantation.

Authors: D. Bohringer, B. Grotejohann, G. Ihorst, H. Reinshagen, E. Spierings, T. Reinhard

Date Published: 13th Apr 2018

Publication Type: Journal

ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286).

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BACKGROUND: Recent randomized controlled trials comparing neoadjuvant chemoradiation plus surgery or perioperative chemotherapy plus surgery with surgery alone showed significant survival benefits for … combined modality treatment of patients with localized esophageal adenocarcinoma. However, head-to-head comparisons of neoadjuvant chemoradiation and perioperative chemotherapy applying contemporary treatment protocols are lacking. The present trial was initiated to obtain valid information whether neoadjuvant chemoradiation or perioperative chemotherapy yields better survival in the treatment of localized esophageal adenocarcinoma. METHODS/DESIGN: The ESOPEC trial is an investigator-initiated multicenter prospective randomized controlled two-arm trial, comparing the efficacy of neoadjuvant chemoradiation (CROSS protocol: 41.4Gy plus carboplatin/paclitaxel) followed by surgery versus perioperative chemotherapy and surgery (FLOT protocol: 5-FU/leucovorin/oxaliplatin/docetaxel) for the curative treatment of localized esophageal adenocarcinoma. Patients with cT1cN + cM0 and cT2-4acNxcM0 esophageal and junctional adenocarcinoma are eligible. The trial aims to include 438 participants who are centrally randomized to one of the two treatment groups in a 1:1 ratio stratified by N-stage and study site. The primary endpoint of the trial is overall survival assessed with a minimum follow-up of 36 months. Secondary objectives are progression-free survival, recurrence-free survival, site of failure, postoperative morbidity and mortality, duration of hospitalization as well as quality of life. DISCUSSION: The ESOPEC trial compares perioperative chemotherapy according to the FLOT protocol to neoadjuvant chemoradiation according to the CROSS protocol in multimodal treatment of non-metastasized recectable adenocarcinoma of the esophagus and the gastroesophageal junction. The goal of the trial is identify the superior protocol with regard to patient survival, treatment morbidity and quality of life. TRIAL REGISTRATION: NCT02509286 (July 22, 2015).

Authors: J. Hoeppner, F. Lordick, T. Brunner, T. Glatz, P. Bronsert, N. Rothling, C. Schmoor, D. Lorenz, C. Ell, U. T. Hopt, J. R. Siewert

Date Published: 19th Jul 2016

Publication Type: Journal

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