Exploratory Clinical Trials Research Articles

Bayesian sample sizes for exploratory clinical trials comparing multiple experimental treatments with a control.

In this paper, a Bayesian approach is developed for simultaneously comparing multiple experimental treatments with a common control treatment in an exploratory clinical trial. The sample size is set to ensure that, at the end of the study, there will be at least one treatment for which the investigators have a strong belief that it is better than control, or else they have a strong belief that none of the experimental treatments are substantially better than control. This criterion bears a direct relationship with conventional frequentist power requirements, while allowing prior opinion to feature in the analysis with a consequent reduction in sample size. If it is concluded that at least one of the experimental treatments shows promise, then it is envisaged that one or more of these promising treatments will be developed further in a definitive phase III trial. The approach is developed in the context of normally distributed responses sharing a common standard deviation regardless of treatment. To begin with, the standard deviation will be assumed known when the sample size is calculated. The final analysis will not rely upon this assumption, although the intended properties of the design may not be achieved if the anticipated standard deviation turns out to be inappropriate. Methods that formally allow for uncertainty about the standard deviation, expressed in the form of a Bayesian prior, are then explored. Illustrations of the sample sizes computed from the new method are presented, and comparisons are made with frequentist methods devised for the same situation.

New medications in development for the treatment of hyperuricemia of gout.

To update recent developments in medications targeting hyperuricemia, but not including medications recently labelled in the European Union and the United States. A new xanthine oxidase inhibitor, Topiloric (Fujiyakuhin Co., Ltd. Japan) Uriadec (Sanwa Kagaku Kenkyusho Co., Ltd. Japan), has been developed and labelled in Japan. An inhibitor of purine nucleoside phosphorylase, Ulodesine, is in development in combination with allopurinol. The rest of the medications in the pipeline for hyperuricemia are targeting renal transporters of uric acid, mainly URAT1 and OAT4, acting as uricosuric agents. Most of them, such as lesinurad and arhalofenate, are being tested in trials in combination with allopurinol and febuxostat. The most potent RDEA3170 is being tested in monotherapy, but also associated with febuxostat. Recently, medications showing dual activity, inhibiting both xanthine oxidoreductase and URAT1, have been communicated or started exploratory clinical trials. There is no report of medications targeting other transporters such as Glut9 or ABCG2. There are a number of medications in the pipeline targeting hyperuricemia, mostly uricosurics in combination with xanthine oxidase inhibitors, but some targeting both xanthine oxidoreductase and URAT1. Increasing the number of available medications will ensure proper control of hyperuricemia to target serum urate levels in the near future for most, if not all, patients with hyperuricemia.

CS-35 * TGF- INDUCES AND BMP SUPPRESSES VEGF RELEASE DEPENDING ON SMAD2/3 VERSUS SMAD1/5/8 SIGNALING IN GLIOBLASTOMA

The transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) and vascular endothelial growth factor (VEGF) pathways have been attributed a major role in the pathogenesis in glioblastoma, but their interactions have remained poorly understood. Thus, we characterized TGF-β/BMP pathway activity in nine long-term glioma cell lines (LTC) and 4 glioma-initiating cell lines (GIC) in relation to constitutive and exogenous TGF-β/BMP-induced VEGF release. As reflected by TGF-β-induced SMAD2/3-phoshorylation and TGF-β/BMP-induced SMAD1/5/8 phosphorylation, glioma cells exhibit heterogeneous patterns of constitutive BMP/TGF-β pathway activation. Constitutive TGF-β pathway activity accounts for up to 69% of constitutive VEGF release which is positively regulated by SMAD2/3 and negatively by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-β induces and exogenous BMP reduces VEGF release in most cell lines. Overall, TGF-β regulates VEGF release by glioma cells in an ALK-5-dependent manner involving SMAD2, SMAD3 and SMAD1/5/8 signaling. This crosstalk between the TGF-β and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials. Beyond, BMP-dependent differentiation therapy as anti-glioma therapy may include VEGF-inhibitory effects.

Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma.

The transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF) pathways have a major role in the pathogenesis of glioblastoma, notably immunosuppression, migration, and angiogenesis, but their interactions have remained poorly understood. We characterized TGF-β pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-β-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data. Glioma cells exhibit heterogeneous patterns of constitutive TGF-β pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-β pathway activity depends on the type I TGF-β receptor, ALK-5, and accounts for up to 69% of constitutive VEGF release, which is positively regulated by SMAD2/3 and negatively regulated by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-β induces VEGF release in most cell lines in a SMAD- and ALK-5-dependent manner. There is no correlation between the fold induction of VEGF secretion induced by TGF-β compared with hypoxia. The role of SMAD5 signaling is highly context and cell-line dependent with a VEGF inhibitory effect at low TGF-β and pSMAD2 levels and a stimulatory effect when TGF-β is abundant. TGF-β regulates VEGF release by glioma cells in an ALK-5-dependent manner involving SMAD2, SMAD3, and SMAD1/5/8 signaling. This crosstalk between the TGF-β and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials focusing on the microenvironment in glioblastoma.

Academic Clinical Trials and Drug Regulations in Japan: Impacts of Introducing the Investigational New Drug System

In Japan, academic clinical trials do not generally need to be conducted under good clinical practice and cannot therefore be used for regulatory submission for marketing authorization of new medical products. We reviewed 2 differential regulatory systems governing clinical trials in Japan and the development histories of 2 case products whose clinical trials at the early development stage were conducted by academic researchers and transferred to the private sector for further development toward commercialization in Japan. We further estimated that the introduction of the investigational new drug system may have accelerated the development of tocilizumab, an antibody drug for rheumatoid arthritis, at best by 2 years by utilizing the results of early exploratory clinical trials conducted by academic investigators. Similarly, an enlarged indication for JACE®, a cultured epithelium autograft for severe burns, would have been expected at launch by utilizing the results of academic trials investigating various indications. These possible impacts and estimations would warrant introducing the investigational new drug system into Japan drug regulatory system.

Alternative strategies for proof-of-principle studies of antibacterial agents.

The proof that a new antibacterial agent is not only active in vitro but also effective in vivo under clinically relevant conditions is currently provided (i) by using appropriate nonclinical models of infection and pharmacokinetic-pharmacodynamic (PK-PD) analysis providing evidence of the likelihood of clinical efficacy and (ii) by examining the study drug in exploratory clinical trials, as well as dose and schedule finding during phase II of clinical development. This approach is both time-consuming and costly. Furthermore, PK-PD targets for any novel antibacterial agent cannot be derived from studies with experimental animals. Therefore, alternative strategies have to be identified to prove the principle that a novel antibacterial agent is active under clinically relevant conditions. This review summarizes evidence that the quantitative analysis of shifts in the viable counts of pathogens in infected patients or the evaluation of the PD effect of an investigational agent on indicator organisms of the human resident microflora or colonizers of healthy volunteers, if paralleled with PK monitoring of serum and the target site, provides an alternative to a classical proof-of-principle study in the course of a phase II study program.

Bio-distribution study of Reolysin® (pelareorep) through a single intravenous infusion in Sprague-Dawley rats

Numerous pre-clinical and clinical studies on reovirus have generated valuable information which supports the use of this orphan virus as an investigational drug for cancer treatment. Reolysin® (pelareorep) is a clinical formulation of the human Reovirus Type 3 Dearing strain. The clinical safety and efficacy of Reolysin® in humans is being tested on an assortment of cancer indications as a mono and/or combination therapy. Reovirus has many inherent characteristics that make it a potential candidate for virotherapy, including: the rapid and natural spread through the haematogenous route, the ability to overcome immunological barriers thereby reaching tumor sites, and being replication-competent. The purpose of this study was to elucidate the bio-distribution pattern of Reolysin® in healthy Sprague-Dawley rats. Following a single 15-min intravenous infusion via the tail vein in Sprague-Dawley rats, the levels of virus genome were determined in 16 organs/tissues by RT-qPCR (Reverse Transcriptase- Quantitative Polymerase Chain Reaction) over a 336 h (Day 15) incubation regime. Consistent with previous studies, maximal reovirus RNA levels were observed in the spleen; indicating its involvement in viral uptake and clearance, followed by heart, ovaries, tail (infusion site), liver and lungs. All the organs/tissues demonstrated unquantifiable levels of reovirus genome at the end of incubation, suggesting substantial to complete viral clearance. Several studies in the last decade have described the use of reovirus for treating ovarian cancers. An increase of reovirus genome in ovaries at 24 h post infection was noted. The results will aid in the design of additional exploratory clinical trials for Reolysin®.

Active post-marketing surveillance of the intralesional administration of human recombinant epidermal growth factor in diabetic foot ulcers

BackgroundAfter several exploratory and confirmatory clinical trials, the intralesional administration of human recombinant epidermal growth factor (hrEGF) has been approved for the treatment of advanced diabetic foot ulcers (DFU). The aim of this work was to evaluate the effectiveness and safety of this procedure in medical practice.MethodsA prospective, post-marketing active pharmacosurveillance was conducted in 41 hospitals and 19 primary care polyclinics. Patients with DFU received hrEGF, 25 or 75 μg, intralesionally 3 times per week until complete granulation of the ulcer or 8 weeks maximum, adjuvant to standard wound care. Outcomes measured were complete granulation, amputations, and adverse events (AE) during treatment; complete lesion re-epithelization and relapses in follow-up (median: 1.2; maximum 4.2 years).ResultsThe study included 1788 patients with 1835 DFU (81% Wagner’s grades 3 or 4; 43% ischemic) treated from May 2007 to April 2010. Complete granulation was observed in 76% of the ulcers in 5 weeks (median). Ulcer non-ischemic etiology (OR: 3.6; 95% CI: 2.8-4.7) and age (1.02; 1.01-1.03, for each younger year) were the main variables with influence on this outcome. During treatment, 220 (12%) amputations (171 major) were required in 214 patients, mostly in ischemic or Wagner’s grade 3 to 5 ulcers. Re-epithelization was documented in 61% of the 1659 followed-up cases; 5% relapsed per year. AE (4171) were reported in 47% of the subjects. Mild or moderate local pain and burning sensation, shivering and chills, were 87% of the events. Serious events, not related to treatment, occurred in 1.7% of the patients.ConclusionsThe favorable benefit/risk balance, confirms the beneficial clinical profile of intralesional hrEGF in the treatment of DFUs.

Research Today

Basic research has identified the 2 major defects linked to polycystic disease: (i) the cystic cells proliferate excessively; (ii) these cells secrete fluid that enlarges the cysts. The main therapeutic strategies in autosomal dominant polycystic kidney disease (ADPKD) are the use of drugs capable of interfering with the mechanisms causing these defects. One of the strategies explored was the inhibition of the mTOR system. Unfortunately, 2 clinical trials have failed to show a protective effect of this class of drugs. Somatostatin is another molecule under intense clinical validation. At the moment, the collected data suggest a possible activity against ADPKD, but the results are still too preliminary to attain clinically meaningful conclusions. Tolvaptan is a vasopressin receptor antagonist that has been extensively studied: a clinical trial recruiting an adequate population suggested a possible positive effect of this molecule in the reduction of renal volume growth and the achievement of significant clinical targets. The near future promises new exploratory clinical trials of molecules that have already been assessed in the recent past or of completely new therapeutic strategies. For the high number of enrolled patients, the HALT study attracts the attention of the scientific community. This trial will explore the role of antagonists of the renin-angiontensin system in slowing the progression of ADPKD. Finally, a category of drugs previously unexplored is that of the inhibitors of the epidermal growth factor receptor. Clinical research in ADPKD is extraordinarily active in this period and this consideration allows a cautious optimism about the prospective therapies for this disease that for long remained orphan. A shadow on the prospect of future results in clinical research in this field comes from the observation that a considerable number of trials show a methodologically inadequate design.

HIV Vaccine Development: Strategies for Preclinical and Clinical Investigation

This article discusses HIV vaccine discovery and candidate vaccine testing in the context of current realities of funding and clinical trial practice. Lacking perfect animal models for testing candidate HIV vaccines, clinical investigators have proposed a strategy of iterative exploratory clinical trials in the model of cancer chemotherapy development. Problems with the appropriateness of this model to HIV vaccine development are discussed. Also, the future feasibility of this strategy in the context of increasing clinical trial costs and emerging new, efficacious prevention modalities is questioned. Strategies for making better use of animal models are presented as an alternative to iterative exploratory clinical efficacy testing. Some ways in which better data from preclinical studies can refine clinical product development are described. Finally, development of an HIV vaccine under the FDA's "Animal Rule" pathway to licensure when human efficacy studies are not feasible is discussed as a fall-back approach. Not making a preventive vaccine against HIV infection is simply not an option because eradication of AIDS will require a preventive vaccine.

SY4-6 - Required Capabilities and Infrastructure for Japanese Phase I Institutes: From the Experience of Early Phase Drug Development Operation at Phase I Centers in United States

ABSTRACT Despite Japanese leadership in basic research and discovery, its prominence in early phase oncology drug development is less established, and frequently, separate trials have been required because of the differing pharmacology of drugs in Asian patients. To date, relatively few first-in-human studies have been conducted in Japan, for the reasons described above with the majority using data from first-in-human studies from other countries to support starting doses. Many first-in-human studies of anticancer drugs are conducted in two sites in different countries, usually in North America (United States or Canada) and the other in Europe. Additional phase I studies including Japanese patients are often required for later marketing approvals in Japan. A number of major initiatives have been implemented since 2004 involving the Pharmaceuticals and Medical Devices Agency (PMDA), and Ministry of Health, Labor and Welfare (MHLW), including initiatives to improve the infrastructure for clinical trials in Japan by supporting clinician researchers (investigators) and medical institutions in conducting clinical trials and developing clinical trial networks. Remarkably, as a new measure to promote early phase clinical studies, the MHLW has been creating infrastructure for early-stage and exploratory clinical trials in Japan since 2011. Given the fact that most Japanese phase I institutes are not sufficiently equipped with effective infrastructures to conduct a fair number of ‘novel’ first-in-human studies, urgent improvements are currently required to strengthen their capabilities. Based on the experience of the phase I operation at START (South Texas Accelerated Research Therapeutics, San Antonio, TX, USA) phase I center, this session will involve discussion of required capabilities for Japanese Phase-I institutes, in addition to introduction of the exemplary Phase-I operation system of US phase I centers.

A Bayesian predictive sample size selection design for single‐arm exploratory clinical trials

The aim of an exploratory clinical trial is to determine whether a new intervention is promising for further testing in confirmatory clinical trials. Most exploratory clinical trials are designed as single-arm trials using a binary outcome with or without interim monitoring for early stopping. In this context, we propose a Bayesian adaptive design denoted as predictive sample size selection design (PSSD). The design allows for sample size selection following any planned interim analyses for early stopping of a trial, together with sample size determination before starting the trial. In the PSSD, we determine the sample size using the method proposed by Sambucini (Statistics in Medicine 2008; 27:1199-1224), which adopts a predictive probability criterion with two kinds of prior distributions, that is, an 'analysis prior' used to compute posterior probabilities and a 'design prior' used to obtain prior predictive distributions. In the sample size determination of the PSSD, we provide two sample sizes, that is, N and N(max) , using two types of design priors. At each interim analysis, we calculate the predictive probabilities of achieving a successful result at the end of the trial using the analysis prior in order to stop the trial in case of low or high efficacy (Lee et al., Clinical Trials 2008; 5:93-106), and we select an optimal sample size, that is, either N or N(max) as needed, on the basis of the predictive probabilities. We investigate the operating characteristics through simulation studies, and the PSSD retrospectively applies to a lung cancer clinical trial. (243)

Seven-Day NIHSS Is a Sensitive Outcome Measure for Exploratory Clinical Trials in Acute Stroke

Clinical trials in stroke typically measure outcome after 90 days. Earlier outcome assessment would reduce costs and may increase power. We aimed to compare the sensitivity of 4 end points (modified Rankin Scale [mRS] at 30 and 90 days, and National Institutes of Health Stroke Scale (NIHSS) at 7 and 90 days, analyzed as ordinal measures) to detect the established treatment effect of recombinant tissue-type plasminogen activator (rtPA). Within the Virtual International Stroke Trials Archive, we compared rtPA-treated patients with untreated control subjects using a multiple resampling approach. From our total sample we drew 10 000 random samples of unique patients, constraining the sample sizes in treated and untreated groups to be equal. In each of these samples we tested for the treatment effect of rtPA by each of the 4 studied end points. The percentage of samples yielding significant results approximates the power of each end point at a given sample size. This process was repeated across a range of sample sizes, to determine the relationship between sample size and power for each of the 4 end points. For our 4 end points of mRS at 30 and 90 days, and NIHSS at 7 and 90 days the smallest sample sizes required to generate statistical power >80% were 620, 480, 370, and 420, respectively, making 7-day NIHSS the most sensitive end point. These results were supported by dichotomized analyses. Seven-day NIHSS score appears a sensitive end point that should be validated in randomized trial datasets for use in exploratory stroke trials.

Abstract 2481: Day 7 NIHSS is a Sensitive Outcome Measure for Exploratory Clinical Trials in Acute Stroke: Evidence from the Virtual International Stroke Trials Archive (VISTA)

Introduction: Clinical trials in stroke typically measure outcome after 90 days. Earlier outcome assessment would reduce costs and may increase power. Aim: To compare the sensitivity of 4 outcome measures (mRS at 30 and 90 days, and NIHSS at 7 and 90 days, analysed as ordinal measures) to the established treatment effect of r-tPA. Methods: We undertook a controlled comparison of r-tPA treated patients versus untreated controls from VISTA. A multiple re-sampling approach was used. From our total sample 10,000 random samples of independent patients were drawn, each of the same size. In each sample ordinal logistic regression (adjusted for age and baseline NIHSS score) was used to test for the r-tPA treatment effect as measured by each of the 4 outcome measures. The percentage of samples yielding significant results approximates the power of each endpoint at a given sample size. This process was repeated across a range of sample sizes. Results: Our data included 4712 patients of whom 1934 (41%) received r-tPA. r-tPA treated patients were younger, and had more severe strokes. For our 4 outcome measures of mRS at 30 and 90 days, and NIHSS at 7 and 90 days the smallest sample sizes required to generate statistical power >80% were 620, 480, 370, and 420 respectively, making 7 day NIHSS the most sensitive endpoint. These results were supported by dichotomised analyses. Conclusions: 7 day NIHSS score appears a sensitive endpoint that should be validated in a randomised trial dataset for use in exploratory stroke trials.

治験薬GMPに基づいた臨床試験用院内無菌製剤室の 設置と適合性評価

Translational research is important for applying the outcomes of basic researches to practical medical treatments. In exploratory clinical trials in the early-phase for an innovative therapy, researchers should often manufacture investigational agents by themselves. To supply investigational agents with safety and high quality in clinical studies, appropriate production management and quality control are essential. In the Department of Pharmacy of Kyoto University Hospital, a manufacturing facility for sterile drugs was established, independent of existing manufacturing facilities. Fifteen manuals about the production management and quality control were enacted. Staff organization based on the enacted manuals was also designated. The facility, manuals and staff organization were evaluated according to good manufacturing practice (GMP) for investigational new drugs (INDs). They were revealed to conform to GMP for INDs except for some clauses. Furthermore, the management of microparticles and microorganisms in the sterile room, referring to the Japanese Pharmacopeia, was determined, and the cleanness was evaluated. A manufacturing facility complying with GMP for INDs was established for supplying high-quality sterile drugs in clinical studies. These achievements can contribute to the safety of patients and reliability in clinical studies.

Multivariate Modelling Reveals Evidence of a Dose-Response Relationship in Phase 2 Studies of Single-Agent Carfilzomib

Abstract 1877▪▪This icon denotes a clinically relevant abstract Introduction:Carfilzomib (CFZ) is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. Phase (ph) 1 and 2 studies with CFZ have demonstrated durable single-agent activity and acceptable safety in patients (pts) with relapsed and/or refractory multiple myeloma (MM). Preliminary side-by-side comparison of efficacy results from PX-171-003-A0 and PX-171-003-A1, 2 studies performed with nearly identical entry criteria and schedules but using different doses of CFZ (20 mg/m2 vs 20/27 mg/m2), suggested a dose–response relationship. The rates of pts achieving either a partial response (PR) or better or a minimal response or better appeared to be greater in 003-A1 than in 003-A0. An analogous comparison of efficacy results from the 2 bortezomib (BTZ)-naïve dosing cohorts (20/27 mg/m2 vs 20 mg/m2) in PX-171-004 revealed similar trends. The present analysis was undertaken to rigorously evaluate the evidence of a potential dose–response relationship for CFZ by employing dose– response modelling. Methods:A pooled multivariate dose–response model was derived using data from the following ph 2 studies of CFZ: 003-A1, 004 (BTZ-naïve), and 004 (BTZ-treated). A multivariate logistic regression analysis for the primary outcome of overall response rate (ORR) was fitted that adjusted for study, CFZ dose, and a broad range of prognostic covariates (eg, cytogenetic status and International Staging System (ISS) stage). In addition, a repeated measures model used generalized estimating equations (GEE) to analyze the association between cycle-specific response status and cycle-specific CFZ dose. Multivariate Cox regression models with the same covariates, stratified by study, were fitted for the time-to-event endpoints (duration of response [DOR], progression-free survival [PFS], and overall survival [OS]). Time-dependent Cox regression models were also fitted for these endpoints using cycle-specific cumulative dose. Results:Evaluation of the effect of actual CFZ dose on the primary efficacy outcome of overall response rate (ORR) demonstrated that the odds of achieving a PR or better for a given pt treated with 27 mg/m2 were 4.08-fold higher (95% CI: 2.30–7.24, P<0.001) than for a pt receiving 20 mg/m2. When using the average dose as a continuous variable and adjusting for study effect, the odds of a response increased by 1.28-fold (95% CI: 1.17–1.40; P<0.001) for each 1 mg/m2 increase in average CFZ dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m2 to 27 mg/m2. Figure 1 presents the dose–response curve for each of the 3 study populations derived by applying the inverse logit transformation to the estimated odds ratio. [Display omitted] Results were similar after adjusting for various baseline prognostic covariates across studies (eg, female gender, higher Hgb level). Multivariate Cox regression models with same prognostic factors were fitted for the secondary efficacy endpoints of DOR, PFS, and OS, and highly significant effects of CFZ dose were again observed.A repeated measures model (using cycle-specific average dose as a dose effect variable) using GEE was applied to remove a potential bias of differential pt characteristics in those receiving higher doses of carfilzomib. In this analysis, the per-cycle odds of an overall response was estimated to increase by 1.12-fold (95% CI: 1.06, 1.18; p<0.001) for each 1 mg/m2 increase in CFZ dose. Additionally, time-dependent Cox regression models were fitted to account for the potential bias due to confounding factors. Results of this analysis confirmed the initial dose–response relationship observed. Conclusions:Preliminary observations of a dose–response relationship for CFZ from ph 2 studies have been confirmed and extended using a statistically rigorous, multivariate analysis. This dose–response relationship is apparent both in terms of the proportion of responding pts across all response endpoints evaluated (ORR, DOR, PFS, and OS) and in the depth of individual responses. While a corresponding dose–toxicity analysis has not been performed to date, carfilzomib has been shown to have a similar tolerability profile when comparing 20 mg/m2 (003-A0) vs 20/27 mg/m2 (003-A1). These findings are being further assessed in exploratory clinical trials (eg, PX-171-007) evaluating higher dosing regimens. Disclosures:Squifflet:International Drug Development Institute: Employment. Michiels:International Drug Development Institute: Consultancy. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Ro:Onyx Pharmaceuticals: Employment, Equity Ownership. Buyse:International Drug Development Institute: Employment, Equity Ownership.

Exploratory clinical trials: A non-clinical drug safety perspective

Exploratory clinical trials: A non-clinical drug safety perspective

New era for drug discovery and development in renal disease

Drug discovery and development is a lengthy and expensive process. Testing new agents in humans at an early stage could reduce the time and costs involved in identifying drugs that are likely to succeed in clinical studies. New guidance has outlined the concept of exploratory clinical trials, which provide important information on a drug's distribution as well as its physiological and pharmacological effects in humans. This strategy reduces the need for preclinical testing by limiting the dose and duration of exposure to a new drug in humans to below those required by the traditional testing of investigational new drugs. Exploratory, first-in-man studies should provide insights into human physiology and pharmacology, identify therapeutic targets relevant to disease and increase our knowledge of a drug's characteristics. Implementation of a new drug also requires the development of useful biomarkers of disease and of the drug's efficacy, as well as sensitive molecular imaging techniques. In this Review, we outline the benefits of exploratory clinical trials, especially in academia, and provide an overview of the experimental tools necessary for rational drug discovery and development.

Multivariate models of Alzheimer's disease progression based on resting-state MEG scans

Resting-state measures of brain function have provided insight into the pathology of CNS diseases, including Alzheimer's disease (AD). We have reported a preliminary analysis of longitudinal resting-state MEG scans conducted in AD patients over the course of 10 months (Verdoorn et al., Alz.Dem. 6: S523-S524, 2010). These results indicated that region-specific changes in brain function significantly correlated with changes in cognitive function measured by neuropsychological testing. Further refinement of data processing methods and analysis now support the development of a robust model of disease progression based on these scans. Data were collected during two exploratory clinical trials that included patients (n = 117) with a previous diagnosis of Dementia of Alzheimer's Type (DSM-IV-TR) and a group of demographically matched healthy control subjects (n = 123). A total of 31 AD patients were tested twice with identical procedures. The evaluations were separated by approximately 10 months. One minute of resting state MEG data were processed to generate time-domain functional connectivity measures based on the SNI test (Georgopoulos et al., 2007, J. NeuralEng. 4: 349) and frequency-domain measures of spectral power. Linear models using combinations of connectivity and spectral power features were generated and tested using standard regression analysis. Significant cross-sectional differences between AD and healthy controls were observed for both global functional connectivity and the global distribution of spectral power. For example, global correlation values increased significantly from 0.12 ± 0.004 in healthy subjects to 0.14 ± 0.004 in AD patients, and centroid frequency of the power density spectrum decreased from 8.24 ± 0.20 Hz in healthy subjects to 6.78 ± 0.25 Hz in AD patients. Longitudinal changes were evaluated by measuring the correlation between changes in MEG scan features and changes in the ADAS-Cog (n = 31 AD patients). Significant correlations were observed between changes in SNI values (c02) and changes in ADAS-Cog (maximum Pearson's r value = 0.79). Similar, albeit weaker, correlations were observed between the centroid frequency of spectral density plots and the ADAS-Cog (maximum r value = -0.43). Linear combinations of centroid frequency and SNI values based on multivariate modeling accurately tracked ADAS-Cog changes with a highly significant r value of 0.99. It was possible to extract and characterize multiple features of resting-state MEG scans that changed in concert with changes in the ADAS-Cog over the course of 10 months. These results demonstrate the utility of resting-state MEG scans for tracking the progression of AD over periods of less than a year. Additional longitudinal testing of this and additional patient cohorts will support continued improvement of disease severity models based on resting-state MEG.

A Biomimetic Membrane Device That Modulates the Excessive Inflammatory Response to Sepsis

ObjectiveSeptic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host's response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis.DesignLaboratory investigation.SettingUniversity of Michigan Medical School.SubjectsPigs weighing 30-35 kg.InterventionsTo assess the effect of the SCD in septic shock, pigs were administered 30×1010 bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD.Measurements and Main ResultsIn this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation.ConclusionsThese preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway.