Franz König

Innovative Approaches for Designing and Analyzing Adaptive Dose-Ranging Trials

Inadequate selection of the dose to bring forward in confirmatory trials has been identified as one of the key drivers of the decreasing success rates observed in drug development programs across the pharmaceutical industry. In recognition of this problem, the Pharmaceutical Research and Manufacturers of America (PhRMA), formed a working group to evaluate and develop alternative approaches to dose finding, including adaptive dose-ranging designs. This paper summarizes the work of the group, including the results and conclusions of a comprehensive simulation study, and puts forward recommendations on how to improve dose ranging in clinical development, including, but not limited to, the use of adaptive dose-ranging methods.

Twenty‐five years of confirmatory adaptive designs: opportunities and pitfalls

‘Multistage testing with adaptive designs’ was the title of an article by Peter Bauer that appeared 1989 in the German journal Biometrie und Informatik in Medizin und Biologie. The journal does not exist anymore but the methodology found widespread interest in the scientific community over the past 25 years. The use of such multistage adaptive designs raised many controversial discussions from the beginning on, especially after the publication by Bauer and Köhne 1994 in Biometrics: Broad enthusiasm about potential applications of such designs faced critical positions regarding their statistical efficiency. Despite, or possibly because of, this controversy, the methodology and its areas of applications grew steadily over the years, with significant contributions from statisticians working in academia, industry and agencies around the world. In the meantime, such type of adaptive designs have become the subject of two major regulatory guidance documents in the US and Europe and the field is still evolving. Developments are particularly noteworthy in the most important applications of adaptive designs, including sample size reassessment, treatment selection procedures, and population enrichment designs. In this article, we summarize the developments over the past 25 years from different perspectives. We provide a historical overview of the early days, review the key methodological concepts and summarize regulatory and industry perspectives on such designs. Then, we illustrate the application of adaptive designs with three case studies, including unblinded sample size reassessment, adaptive treatment selection, and adaptive endpoint selection. We also discuss the availability of software for evaluating and performing such designs. We conclude with a critical review of how expectations from the beginning were fulfilled, and – if not – discuss potential reasons why this did not happen.

Lithium in the public water supply and suicide mortality in Texas

There is increasing evidence from ecological studies that lithium levels in drinking water are inversely associated with suicide mortality. Previous studies of this association were criticized for using inadequate statistical methods and neglecting socioeconomic confounders. This study evaluated the association between lithium levels in the public water supply and county-based suicide rates in Texas. A state-wide sample of 3123 lithium measurements in the public water supply was examined relative to suicide rates in 226 Texas counties. Linear and Poisson regression models were adjusted for socioeconomic factors in estimating the association. Lithium levels in the public water supply were negatively associated with suicide rates in most statistical analyses. The findings provide confirmatory evidence that higher lithium levels in the public drinking water are associated with lower suicide rates. This association needs clarification through examination of possible neurobiological effects of low natural lithium doses.

Osteopontin expression predicts overall survival after liver transplantation for hepatocellular carcinoma in patients beyond the Milan criteria

BACKGROUND & AIMS Microarray data showed that osteopontin overexpression predicts early HCC-recurrence after liver resection. Osteopontin (OPN) expression could serve as a predictor of HCC-recurrence after OLT. METHODS Osteopontin expression was investigated immunohistochemically in a unique population of 125 HCC-patients undergoing OLT between 1982 and 2002, including 81 patients (65%) outside the Milan criteria. Multivariate analysis of factors associated with median overall survival (OS) and time to recurrence (TTR) was performed. RESULTS Osteopontin was expressed in 40/125 (32%) of the HCCs. Overall survival post-OLT at 1, 2, 3, 5 years was 77%, 62%, 52%, and 43% (median survival 37 months). Overall survival was significantly longer without expression of OPN (p < 0.05; (median OS: 56 vs. 23 months). The same was true for median TTR (p = 0.008). Outside Milan criteria, patients without OPN-expression had better prognosis (median OS: 37.8 vs. 19.2 months, p = 0.003). Tumor recurrence in patients transplanted outside Milan criteria occurred in 43% (23 of 54) of patients without and 70% (19 of 27, p = 0.018) of patients with OPN-expression after a median TTR of 83.5 vs. 13.9 months. On multivariate analysis, vascular invasion and OPN-expression were independently associated with OS and TTR in HCC-patients after OLT. CONCLUSIONS Immunohistochemically detectable Osteopontin in HCC is an independent predictor of tumor recurrence and survival in patients beyond Milan criteria undergoing OLT.

A double‐blind, randomized, placebo‐controlled trial of intravenous l‐ornithine–l‐aspartate on postural control in patients with cirrhosis

Introduction: Hepatic encephalopathy (HE) is a complication of liver disease. Several treatments have been introduced but only l‐ornithine–l‐aspartate (LOLA) shows proven efficacy. This double‐blind, randomized, placebo‐controlled trial evaluated the effect of LOLA on postural control in cirrhotics.

Diagnostic Contribution of Donor-specific Antibody Characteristics to Uncover Late Silent Antibody-mediated Rejection—results of a Cross-sectional Screening Study

Background Circulating donor-specific antibodies (DSA) detected on bead arrays may not inevitably indicate ongoing antibody-mediated rejection (AMR). Here, we investigated whether detection of complement-fixation, in parallel to IgG mean fluorescence intensity (MFI), allows for improved prediction of AMR. Methods Our study included 86 DSA+ kidney transplant recipients subjected to protocol biopsy, who were identified upon cross-sectional antibody screening of 741 recipients with stable graft function at 6 months or longer after transplantation. IgG MFI was analyzed after elimination of prozone effect, and complement-fixation was determined using C1q, C4d, or C3d assays. Results Among DSA+ study patients, 44 recipients (51%) had AMR, 24 of them showing C4d-positive rejection. Although DSA number or HLA class specificity were not different, patients with AMR or C4d + AMR showed significantly higher IgG, C1q, and C3d DSA MFI than nonrejecting or C4d-negative patients, respectively. Overall, the predictive value of DSA characteristics was moderate, whereby the highest accuracy was computed for peak IgG MFI (AMR, 0.73; C4d + AMR, 0.71). Combined analysis of antibody characteristics in multivariate models did not improve AMR prediction. Conclusions We estimate a 50% prevalence of silent AMR in DSA+ long-term recipients and conclude that assessment of IgG MFI may add predictive accuracy, without an independent diagnostic advantage of detecting complement-fixation.

Cytotoxicity of a calcium aluminate cement in comparison with other dental cements and resin-based materials

The objective of this study was to compare the cytotoxic effects of a calcium aluminate cement with several currently used direct restorative materials. Specimens of three composites (QuiXfil, Tetric Ceram, Filtek Supreme), one zinc phosphate cement (Harvard Cement), one glass ionomer cement (Ketac Molar), and one calcium aluminate cement (DoxaDent), were used fresh or after 7-days’ preincubation in cell culture medium at 37°C, pH 7.2. PVC strips for ISO 10993-5 cytotoxicity test were used as positive control and glass specimens as negative control. L-929 fibroblasts (5-ml aliquots, containing 3×104 cells/ml), cultivated in DMEM with 10% FCS, 1% glutamine, and 1% penicillin/streptomycin at 37°C/5% CO2 and trypsinized, were exposed to the specimens for 72 h. The cells were harvested, centrifuged, and resuspended in 500 µl DMEM and then counted in 500 µl DMEM for 30 s with a flow cytometer at 488 nm. The analysis of variance comparing the six materials showed different influences on L-929 fibroblast cytotoxicity (p<0.0001). The cytotoxicity of all specimens diminished with increasing preincubation time (p<0.0001). Fresh DoxaDent exhibited the lowest cytotoxicity, followed by QuiXfil. Ketac Molar showed the highest cytotoxicity. After 7 days of preincubation, Harvard Cement and Filtek Supreme demonstrated more cytotoxicity than the other materials (p<0.005).

The impact of colony-stimulating factor-1 on fracture healing: an experimental study.

The role of colony stimulating factor‐1 (CSF‐1) in the regulation of osteoclasts and bone remodeling suggests that CSF‐1 may also be involved in regulation of bone healing. The ability of CSF‐1 to promote healing of bone defects was tested in a rabbit model. Twenty‐four New Zeeland rabbits were included in the study. Animals were assigned to two groups: the control group (n = 12) was treated by plate fixation. The animals in the second group (n = 12) were also stabilized by conventional plating and received additionally CSF‐1 for 2 weeks systemically. Histologic, histomorphometric, and radiologic examinations were performed to evaluate the healing process at 4, 8, and 12 weeks following surgery. Animals that were treated by CSF‐1 produced a significantly higher amount of mineralized bone over the first 8 weeks after fracture compared to the control animals. Furthermore, a higher number of osteoclasts was found in CSF‐1‐treated animals within the first 8 weeks, compared to the controls. The present data emphasize for the first time the importance of CSF‐1 in the bone healing. The use of CSF‐1 in addition to conventional fixation might be a novel approach for the treatment of bone defects.

Cytotoxicity and shear bond strength of four orthodontic adhesive systems.

The objective of this study was to compare the cytotoxicity of four orthodontic bonding systems, Light Bond, Enlight, Concise, and Transbond, and to evaluate their shear bond strength (SBS). These orthodontic bonding materials were applied to metal brackets (Mini Diamond). Glass specimens were used as controls in all experiments. Only Concise was a chemically cured system, the other systems were light cured. The specimens were added to L-929 fibroblast cultures immediately after fabrication or after pre-incubation for 7 days. The incubation time was 72 hours and the cells were counted by flow cytometry. One hundred and fifty-seven freshly extracted human third molars were used for testing the SBS in a universal testing machine. Statistical significance was determined using analysis of variance followed by post hoc comparisons for multiple-level alpha control. Pairwise comparisons showed a significant difference only between Light Bond and Concise (P = 0.0126). The highest SBS was obtained with Light Bond (23.23 +/- 1.53 MPa) followed by Transbond (20.39 +/- 1.18 MPa) and Enlight, (20.32 +/- 1.06 MPa). Concise (17.87 +/- 1.04 MPa) showed the lowest SBS. The cytotoxicity of all light-cured systems for fresh specimens was comparable, whereas the chemically cured system, Concise, was significantly more cytotoxic. After 7 days of pre-incubation, all systems were significantly less cyotoxic than fresh specimens (P < 0.001). Brackets alone were not cytotoxic. All bonding systems showed a clinically satisfactory bond strength higher than 10 MPa, with the chemically cured system showing the lowest SBS.

Combination of anorganic bovine‐derived hydroxyapatite with binding peptide does not enhance bone healing in a critical‐size defect in a rabbit model

Anorganic bovine‐derived hydroxyapatite (ABM) in combination with binding peptid (P‐15) has demonstrated the capacity to improve the healing of periodontal defects. This study evaluated the benefit of ABM/P‐15 to promote healing of cortical long bone defects in a rabbit model. A 5‐mm segmental bone defect was created in the femur and fixed with a plate. There were two treatment groups: no implant (n = 12) and ABM/P‐15 (n = 12). At 4, 8, and 12 weeks, healing of the defect was evaluated with radiographs and histomorphometric examination of the treated femora. After 4 weeks, radiographs showed bone formation without signs of complete consolidation in three of four animals in the control group and two of four ABM/P‐15 treated animals. At the later course of the treatment, no radiologic difference was evident between the treatment groups. Histomorphometric evaluation revealed an area of 1.29 ± 0.11 mm2 and 0.97 ± 0.21 mm2 of newly produced bone in animals of the control group and ABM/P‐15 group after 4 weeks. After 8 and 12 weeks, animals in the control group had an area of 2.44 ± 0.62 mm2 and 2.5 ± 0.2 mm2 of newly produced bone within the osteotomy gap compared to 1.6 ± 0.65 mm2 and 1.56 ± 0.27 mm2 in the ABM/P‐15 group (p = 0.0004). An enhanced or accelerated ingrowth of bone, as reported in previous studies, was not observed. Our results imply that the ABM/P‐15 is not a suitable graft for the treatment of critical‐sized segmental defects in long bones.