Evaluation of the drug-drug interaction potential of treosulfan using a physiologically-based pharmacokinetic modelling approach.

AIMS: The aim of this work is the development of a mechanistic physiologically-based pharmacokinetic (PBPK) model using in vitro to in vivo extrapolation to conduct a drug-drug interaction (DDI) assessment of treosulfan against two cytochrome p450 (CYP) isoenzymes and P-glycoprotein (P-gp) substrates. METHODS: A PBPK model for treosulfan was developed de novo based on literature and unpublished clinical data. The PBPK DDI analysis was conducted using the U.S. Food and Drug Administration (FDA) DDI index drugs (probe substrates) midazolam, omeprazole and digoxin for CYP3A4, CYP2C19 and P-gp, respectively. Qualified and documented PBPK models of the probe substrates have been adopted from an open-source online model database. RESULTS: The PBPK model for treosulfan, based on both in vitro and in vivo data, was able to predict the plasma concentration-time profiles and exposure levels of treosulfan applied for a standard conditioning treatment. Medium and low potentials for DDI on CYP3A4 (maximum area under the concentration-time curve ratio (AUCRmax = 2.23) and CYP2C19 (AUCRmax = 1.6) were predicted, respectively, using probe substrates midazolam and omeprazole. Treosulfan was not predicted to cause a DDI on P-gp. CONCLUSION: Medicinal products with a narrow therapeutic index (eg, digoxin) that are substrates for CYP3A4, CYP2C19 or P-gp should not be given during treatment with treosulfan. However, considering the comprehensive treosulfan-based conditioning treatment schedule and the respective pharmacokinetic properties of the concomitantly used drugs (eg, half-life), the potential for interaction on all evaluated mechanisms would be low (AUCR < 1.25), if concomitantly administered drugs are dosed either 2 hours before or 8 hours after the 2-hour intravenous infusion of treosulfan.

Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 × 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 × 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

Statistical analysis of rare sequence variants: an overview of collapsing methods.

With the advent of novel sequencing technologies, interest in the identification of rare variants that influence common traits has increased rapidly. Standard statistical methods, such as the Cochrane-Armitage trend test or logistic regression, fail in this setting for the analysis of unrelated subjects because of the rareness of the variants. Recently, various alternative approaches have been proposed that circumvent the rareness problem by collapsing rare variants in a defined genetic region or sets of regions. We provide an overview of these collapsing methods for association analysis and discuss the use of permutation approaches for significance testing of the data-adaptive methods.

Quality control issues and the identification of rare functional variants with next-generation sequencing data.

Next-generation sequencing of large numbers of individuals presents challenges in data preparation, quality control, and statistical analysis because of the rarity of the variants. The Genetic Analysis Workshop 17 (GAW17) data provide an opportunity to survey existing methods and compare these methods with novel ones. Specifically, the GAW17 Group 2 contributors investigate existing and newly proposed methods and study design strategies to identify rare variants, predict functional variants, and/or examine quality control. We introduce the eight Group 2 papers, summarize their approaches, and discuss their strengths and weaknesses. For these investigations, some groups used only the genotype data, whereas others also used the simulated phenotype data. Although the eight Group 2 contributions covered a wide variety of topics under the general idea of identifying rare variants, they can be grouped into three broad categories according to their common research interests: functionality of variants and quality control issues, family-based analyses, and association analyses of unrelated individuals. The aims of the first subgroup were quite different. These were population structure analyses that used rare variants to predict functionality and examine the accuracy of genotype calls. The aims of the family-based analyses were to select which families should be sequenced and to identify high-risk pedigrees; the aim of the association analyses was to identify variants or genes with regression-based methods. However, power to detect associations was low in all three association studies. Thus this work shows opportunities for incorporating rare variants into the genetic and statistical analyses of common diseases.

Observation and execution of upper-limb movements as a tool for rehabilitation of motor deficits in paretic stroke patients: protocol of a randomized clinical trial.

BACKGROUND: Evidence exist that motor observation activates the same cortical motor areas that are involved in the performance of the observed actions. The so called "mirror neuron system" has been proposed to be responsible for this phenomenon. We employ this neural system and its capability to re-enact stored motor representations as a tool for rehabilitating motor control. In our new neurorehabilitative schema (videotherapy) we combine observation of daily actions with concomitant physical training of the observed actions focusing on the upper limbs. Following a pilot study in chronic patients in an ambulatory setting, we currently designed a new multicenter clinical study dedicated to patients in the sub-acute state after stroke using a home-based self-induced training. Within our protocol we assess 1) the capability of action observation to elicit rehabilitational effects in the motor system, and 2) the capacity of this schema to be performed by patients without assistance from a physiotherapist. The results of this study would be of high health and economical relevance. METHODS/DESIGN: A controlled, randomized, multicenter, paralleled, 6 month follow-up study will be conducted on three groups of patients: one group will be given the experimental treatment whereas the other two will participate in control treatments. All patients will undergo their usual rehabilitative treatment beside participation in the study. The experimental condition consists in the observation and immediate imitation of common daily hand and arm actions. The two parallel control groups are a placebo group and a group receiving usual rehabilitation without any trial-related treatment. Trial randomization is provided via external data management. The primary efficacy endpoint is the improvement of the experimental group in a standardized motor function test (Wolf Motor Function Test) relative to control groups. Further assessments refer to subjective and qualitative rehabilitational scores. This study has been reviewed and approved by the ethics committee of Aachen University. DISCUSSION: This therapy provides an extension of therapeutic procedures for recovery after stroke and emphasizes the importance of action perception in neurorehabilitation The results of the study could become implemented into the wide physiotherapeutic practice, for example as an ad on and individualized therapy.

Metachronous metastasis- and survival-analysis show prognostic importance of lymphadenectomy for colon carcinomas.

BACKGROUND: Lymphadenectomy is performed to assess patient prognosis and to prevent metastasizing. Recently, it was questioned whether lymph node metastases were capable of metastasizing and therefore, if lymphadenectomy was still adequate. We evaluated whether the nodal status impacts on the occurrence of distant metastases by analyzing a highly selected cohort of colon cancer patients. METHODS: 1,395 patients underwent surgery exclusively for colon cancer at the University of Lübeck between 01/1993 and 12/2008. The following exclusion criteria were applied: synchronous metastasis, R1-resection, prior/synchronous second carcinoma, age < 50 years, positive family history, inflammatory bowel disease, FAP, HNPCC, and follow-up < 5 years. The remaining 421 patients were divided into groups with (TM+, n = 75) or without (TM-, n = 346) the occurrence of metastasis throughout a 5-year follow-up. RESULTS: Five-year survival rates for TM + and TM- were 21% and 73%, respectively (p < 0.0001). Survival rates differed significantly for N0 vs. N2, grading 2 vs. 3, UICC-I vs. -II and UICC-I vs. -III (p < 0.05). Regression analysis revealed higher age upon diagnosis, increasing N- and increasing T-category to significantly impact on recurrence free survival while increasing N-and T-category were significant parameters for the risk to develop metastases within 5-years after surgery (HR 1.97 and 1.78; p < 0.0001). CONCLUSIONS: Besides a higher T-category, a positive N-stage independently implies a higher probability to develop distant metastases and correlates with poor survival. Our data thus show a prognostic relevance of lymphadenectomy which should therefore be retained until conclusive studies suggest the unimportance of lmyphadenectomy.

Tumor necrosis factor-α promoter -308 G/A polymorphism and susceptibility to sepsis in very-low-birth-weight infants.

OBJECTIVES: To determine whether the tumor necrosis factor-α -308 G/A polymorphism is associated with blood culture-proven sepsis in two large cohorts of very-low-birth-weight infants. DESIGN: Genetic association studies. SETTING: Prospective, population-based, multicentered cohort of 1944 very-low-birth-weight infants born in 14 German study centers between 2003 and 2008 and 976 mothers, and a second prospective cohort of 926 very-low-birth-weight infants born in 2009 (German Neonatal Network). MEASUREMENTS AND MAIN RESULTS: In cohort I, 344 of 1944 (18.2%) very-low-birth-weight infants had at least one episode of blood culture-proven sepsis develop. The sepsis incidence stratified to genotype was 19.3% for G/G, 15.8% for G/A, 10.0% for A/A genotype (Cochrane-Armitage trend test: G/G vs. G/A: odds ratio, 1.32; 95% confidence interval, 1.03-1.71; G/G vs. A/A: odds ratio, 1.74; 95% confidence interval, 1.06-2.91; p = .03). There was a trend for association of tumor necrosis factor-α -308 A/G genotype with late-onset sepsis episodes (incidence: 17.2% for G/G, 12.5% for G/A, 10.0% for A/A genotype; Cochrane-Armitage trend test: G/G vs. G/A: odds ratio, 1.43; 95% confidence interval, 1.09-1.9; G/G vs. A/A: odds ratio, 2.05; 95% confidence interval, 1.19-3.56; p = .009). However, after adjustment for multiple testing, no significant associations were found. Furthermore, the genotype of the investigated 976 mothers had no impact on sepsis risk for their very-low-birth-weight infants. We additionally studied a second prospective cohort of 926 very-low-birth-weight infants and found no associations with sepsis risk. CONCLUSIONS: No association was found between the tumor necrosis factor-α -308 G/A polymorphism blood culture-proven sepsis in two large cohorts of very-low-birth-weight infants. A recent meta-analysis demonstrated that the tumor necrosis factor-α -308 A allele is associated with higher sepsis risk in adult cohorts. Thus, potential differences between adults and infants need to be incorporated in future study designs evaluating risk profiles for sepsis.

Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies.

Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.

Multiple test procedures using an upper bound of the number of true hypotheses and their use for evaluating high-dimensional EEG data.

Frequency analyses of EEG data yield large data sets, which are high-dimensional and have to be evaluated statistically without a large number of false positive statements. There exist several methods to deal with this problem in multiple comparisons. Knowing the number of true hypotheses increases the power of some multiple test procedures, however the number of true hypotheses is unknown, in general, and must be estimated. In this paper, we derive two new multiple test procedures by using an upper bound for the number of true hypotheses. Our first procedure controls the generalized family-wise error rate, and thus is an improvement of the step-down procedure of Hommel and Hoffmann [Hommel G., Hoffmann T. Controlled uncertainty. In: Bauer P. Hommel G. Sonnemann E., editors. Multiple Hypotheses Testing, Heidelberg: Springer 1987;ISBN 3540505598:p. 154-61]. The second new procedure controls the false discovery proportion and improves upon the approach of Lehmann and Romano [Lehmann E.L., Romano J.P. Generalizations of the familywise error rate. Ann. Stat. 2005;33:1138-54]. By Monte-Carlo simulations, we show how the gain in power depends upon the accuracy of the estimate of the number of true hypotheses. The gain in power of our procedures is demonstrated in an example using EEG data on the processing of memorized lexical items.

Characteristic functional networks in high- versus low-proficiency second language speakers detected also during native language processing: an explorative EEG coherence study in 6 frequency bands.

An EEG coherence study was performed with a twofold objective: first, to scrutinize the theoretical concept of "cortical efficiency" in connection with second language (L2) acquisition and, second, to detect cooperations between cortical areas in specific frequency bands indicative for highly proficient L2 processing. Two groups differing only in their level of L2 proficiency were contrasted during presentation of natural language videos in English (L2) and German (native language, L1), with explorative coherence analysis in 6 frequency bands (0.5-31.5 Hz). The coherence brain maps revealed more pronounced and widespread increases in coherences in the alpha1-band (8-10 Hz) in low-proficiency than in the high-proficiency L2 speakers. Surprisingly, this difference was obtained also during L1 processing and corroborated for both languages by multivariate permutation tests. These tests revealed additional differences between the low- and the high-proficiency group also for coherences within the beta1- (13-18 Hz) and the beta2-band (18.5-31.5 Hz), again during L2 and L1 processing. Since the same group differences were observed during L1 and L2 processing, our high-proficiency group might have profited from a more generic advantage in language or text processing strategy. This strategic advantage was most evident at alpha1 frequencies, possibly related to a specific way of processing internal mental states (top-down processing).

Multivariate tests for the evaluation of high-dimensional EEG data.

In this paper several multivariate tests are presented, in particular permutation tests, which can be used in multiple endpoint problems as for example in comparisons of high-dimensional vectors of EEG data. We have investigated the power of these tests using artificial data in simulations and real EEG data. It is obvious that no one multivariate test is uniformly most powerful. The power of the different methods depends in different ways on the correlation between the endpoints, on the number of endpoints for which differences exist and on other factors. Based on our findings, we have derived rules of thumb regarding under which configurations a particular test should be used. In order to demonstrate the properties of different multivariate tests we applied them to EEG coherence data. As an example for the paired samples case, we compared the 171-dimensional coherence vectors observed for the alpha1-band while processing either concrete or abstract nouns and obtained significant global differences for some sections of time. As an example for the unpaired samples case, we compared the coherence vectors observed for language students and non-language students who processed an English text and found a significant global difference.

Analysis of gastrin-releasing peptide gene and gastrin-releasing peptide receptor gene in patients with agoraphobia.

A gastrin-releasing peptide receptor (GRPR) knock-out mouse model provided evidence that the gastrin-releasing peptide (GRP) and its neural circuitry operate as a negative feedback-loop regulating fear, suggesting a novel candidate mechanism contributing to individual differences in fear-conditioning and associated psychiatric disorders such as agoraphobia with/without panic disorder. Studies in humans, however, provided inconclusive evidence on the association of GRP and GRPR variations in agoraphobia with/without panic disorder. Based on these findings, we investigated whether GRP and GRPR variants are associated with agoraphobia. Mental disorders were assessed via the Munich-Composite International Diagnostic Interview (M-CIDI) in 95 patients with agoraphobia with/without panic disorder and 119 controls without any mental disorders. A complete sequence analysis of GRP and GRPR was performed in all participants. We found no association of 16 GRP and 7 GRPR variants with agoraphobia with/without panic disorder.

Polymorphisms in FTO and MAF Genes and Birth Weight, BMI, Ponderal Index, Weight Gain in a Large Cohort of Infants with a Birth Weight below 1500 Grams.

BACKGROUND: The FTO gene, located on chromosome 16q12.2, and the MAF gene, located on chromosome 16q22-23, were identified as genes harboring common variants with an impact on obesity predisposition. We studied the association of common variants with birth weight, gain of body weight, body mass index (BMI), Ponderal index and relevant neonatal outcomes in a large German cohort of infants with a birth weight below 1500 grams. METHODS: The single nucleotide polymorphisms rs9939609 (FTO gene) and rs1424233 (MAF gene) were genotyped using allelic discrimination assays in a prospective multicenter cohort study conducted in 15 neonatal intensive care units in Germany from September 2003 until January 2008. DNA samples were extracted from buccal swabs according to standard protocols. RESULTS: 1946 infants were successfully genotyped at FTO and 2149 infants at MAF. Allele frequencies were not significantly different from other European cohorts. The polymorphisms were in Hardy-Weinberg equilibrium. The polymorphisms did not show associations with birth weight, BMI and Ponderal Index at discharge, and weight gain, neither testing for a dominant, additive nor for a recessive model. DISCUSSION: Since an association of the polymorphisms with weight gain has been demonstrated in multiple populations, the lack of association in a population of preterm infants with regular tube feeding after birth and highly controlled feeding volumes provides evidence for the hypothesis that these polymorphisms affect food intake behavior and hunger rather than metabolism and energy consumption.

[Utility of medical devices: approaches to planning and conducting clinical trials]. / Nutzen von Medizinprodukten: Lösungsansätze bei der Planung und Durchführung von Studien.

Medicines and medical devices do not only differ in the approval process, but also in the aim and conduct of clinical trials. We first discuss important differences between medicinal products and medical devices. Emphasis is put on the differences in the framework for clinical trials. We point out that a different analysis set should be used in clinical trials of medical devices when compared with medicinal products and medical devices in the USA. Specifically, regulators generally ask for the full analysis set based on the intention-to-treat principle as proof of efficacy of medicines. A central aspect of clinical trials of medical devices is that they have to be tested under normal conditions of use according to the performance data. As a result, all data acquired while the medical device was not during normal conditions of use should be excluded from statistical analyses. We discuss statistical methodological particularities of medical devices, such as blinding and the control of placebo effects. Using the conservative treatment of anal incontinence as an example, we show that comprehensive technical and physical knowledge is required for assessing the utility of medical devices. Finally, we consider reporting of severe adverse events and of severe adverse device effects of medical devices.

Radioprotective effect of lidocaine on function and ultrastructure of salivary glands receiving fractionated radiation.

PURPOSE: Radiation-induced xerostomia still represents a common side effect after radiotherapy for head-and-neck malignancies. The aim of the present study was to examine the radioprotective effect of lidocaine hydrochloride during fractionated radiation in an experimental animal model. METHODS AND MATERIALS: To evaluate the influence of different radiation doses on salivary gland function and the radioprotective effect of lidocaine, rabbits were irradiated with 15, 25, 30, and 35 Gy (equivalent doses in 2-Gy fractions equivalent to 24, 40, 48, and 56 Gy, respectively). Lidocaine hydrochloride (10 and 12 mg/kg) was administered before every radiation fraction in the treatment groups. Salivary gland function was assessed by flow sialometry and sialoscintigraphy, and the morphologic changes were evaluated using transmission electron microscopy. RESULTS: Functional impairment was first observed after 35 Gy and pretreatment with lidocaine improved radiation tolerance of both parotid and submandibular glands. The use of 12 mg/kg lidocaine was superior and displayed significant radioprotection with regard to flow sialometry and sialoscintigraphy. The ultrastructure was largely preserved after pretreatment with both lidocaine doses. CONCLUSIONS: Lidocaine represents an effective radioprotective agent and a promising approach for clinical application to avoid radiation-induced functional impairment of salivary glands.

Incidence of therapy-related acute leukaemia in mitoxantrone-treated multiple sclerosis patients in Germany.

BACKGROUND: The incidence of therapy-related acute leukaemia (TRAL) in mitoxantrone treatment in multiple sclerosis (MS) is controversially discussed. METHODS AND RESULTS: In a retrospective meta-analysis from six centres, we observed six cases of acute myeloid leukaemia (AML) (incidence 0.41% for patients with mean follow up after end of treatment of 3.6 years, n = 1.156; incidence 0.25% for all patients, n = 2.261). Potential influencing factors such as myelotoxic or glucocorticosteroid pretreatment/cotreatment were present in all but one case of TRAL. Between 1990 and 2010, 11 cases of TRAL were reported to the Drug Commission of the German Medical Association (estimated risk of 0.09-0.13%). CONCLUSIONS: Regional differences in reported TRAL incidence may point to confounding cofactors such as administration protocols and cotreatments.

Epidemic microclusters of blood-culture proven sepsis in very-low-birth weight infants: experience of the German Neonatal Network.

INTRODUCTION: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010. METHODS: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. RESULTS: In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. DISCUSSION: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care.

Comparison of collapsing methods for the statistical analysis of rare variants.

Novel technologies allow sequencing of whole genomes and are considered as an emerging approach for the identification of rare disease-associated variants. Recent studies have shown that multiple rare variants can explain a particular proportion of the genetic basis for disease. Following this assumption, we compare five collapsing approaches to test for groupwise association with disease status, using simulated data provided by Genetic Analysis Workshop 17 (GAW17). Variants are collapsed in different scenarios per gene according to different minor allele frequency (MAF) thresholds and their functionality. For comparing the different approaches, we consider the family-wise error rate and the power. Most of the methods could maintain the nominal type I error levels well for small MAF thresholds, but the power was generally low. Although the methods considered in this report are common approaches for analyzing rare variants, they performed poorly with respect to the simulated disease phenotype in the GAW17 data set.

Triple-target treatment versus low-frequency electrostimulation for anal incontinence: a randomized, controlled trial.

BACKGROUND: In the nonsurgical treatment of anal incontinence, the combination of amplitude-modulated medium-frequency stimulation and electromyographic biofeedback (EMG-BF), known as triple-target treatment (3T), is superior to EMG-BF alone. The aim of this trial is to compare 3T with the standard treatment, low-frequency stimulation (LFS). METHODS: 80 patients with anal incontinence of Grade I or higher who presented to physicians or centers specialized in coloproctology were enrolled in this multicenter randomized trial with blinded observer. The trial had an open parallel-group design. Randomization was performed centrally by telephone. The primary endpoint was the Cleveland Clinic Score (CCS) after self-training at home with either 3T or LFS in two 20-minute sessions per day for 6 months. The secondary endpoints included the proportion of patients regaining continence, and the patients' quality of life (QoL). On completion of the trial as planned, the results were evaluated with an intention-to-treat analysis. STUDY REGISTRATION: DRKS00000138 (http://register.germanctr.de). RESULTS: 39 patients were randomized to 3T, and 41 to LFS. After 6 months of treatment, the CCS (mean ± standard deviation) was 3.1 ± 4.2 in the 3T group and 9.6 ± 3.9 in the LFS group. The median improvement in the CCS at 6 months compared to baseline was 7 points greater in the 3T group than in the LFS group (95% CI: 5-9, p<0.001). Anal continence was regained by 54% of the 3T patients, but none of the LFS patients (95% CI for the difference: 37.18% - 69.91%, p<0.001). QoL scores were higher in all dimensions in the 3T group than in the LFS group. No major adverse effects occurred in either group. CONCLUSION: 3T is superior to LFS in the treatment of anal incontinence. The available evidence suggests that the success of 3T is based on the combined effect of biofeedback and medium-frequency stimulation. LFS of the type applied in this trial has no effect. 3T should be used in routine clinical practice instead of LFS.