Proof Of Concept Phase Research Articles

SNG100, a novel topical treatment for moderate atopic dermatitis, in patients aged 6years or older: A randomised, double-blind, active-controlled trial.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. It is associated with significant itch and impaired quality of life. Systemic treatments are efficient but associated with side effects. Novel topical treatments with a favourable safety profile are needed. SNG100 is a novel composition of hydrocortisone 1% in a cream base comprising sulphated polysaccharide (SPS; extracted from in-house cultivated Porphyridium Cruentum unicellular algae), a well-known hydrating, moisturising and a skin barrier repairing agent. To assess the safety, usability and efficacy of SNG100 cream in patients aged ≥6years with moderate AD. In this proof of concept phase I, double-blind, randomised trial, participants received one of three treatments for 14days: SNG100 twice daily (BID), hydrocortisone 1% BID or mometasone furoate once daily (QD). The primary endpoint was the safety and tolerability of SNG100 cream compared to hydrocortisone 1% and mometasone furoate. The secondary endpoint was the subject's usability of SNG100. Exploratory efficacy endpoints included percent change from baseline in SCOring AD (SCORAD), Eczema Area and Severity Index, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, pruritus Numerical Rating Score (NRS), peak pruritus-NRS and Investigator's Global Assessment. Subjects were also followed up without any treatment for additional 14days. Overall, 66 participants were screened, and 60 patients were randomised. SNG100 demonstrated a high safety profile, similar to marketed products hydrocortisone 1% and mometasone furoate 0.1%, with no unanticipated drug safety related events. SNG100 and mometasone furoate 0.1% cream achieved almost similar and statistically significant greater percentage reductions from baseline in SCORAD as compared to hydrocortisone 1% cream. SNG100 demonstrated significant improvement in NRS as compared to hydrocortisone 1% cream. Remarkably, SNG100 led to a lasting effect with only 29.4% of subjects returning to IGA3 during the follow-up period compared to 50% and 38.9% in the hydrocortisone 1% and in mometasone furoate treatment arms, respectively. Topical SNG100 is an effective, safe, and well-tolerated innovative treatment for moderate AD. Trial registration number: NCT04615962 (Topical Cream SNG100 for Treatment in Moderate AD Subjects).

Supramolecular Halogen Bonds in Asymmetric Catalysis.

Halogen bonding has received a significant increase in attention in the past 20 years. An important part of this interest has centered on catalytic applications of halogen bonding. Halogen bond (XB) catalysis is still a developing field in organocatalysis, although XB catalysis has outgrown its proof of concept phase. The start of this year witnessed the publication of the first example of a purely XB-based enantioselective catalytic reaction. While the selectivity can be improved upon, there are already plenty of examples in which halogen bonds, among other interactions, play a crucial role in the outcome of highly enantioselective reactions. This paper will give an overview of the current state of the use of XBs in catalytic stereoselective processes.

Early clinical management of severe burn patients using telemedicine: a pilot study protocol

BackgroundEmergency physicians are responsible for assessing the severity of a patient’s burns, which determines whether the patient needs to be transferred to a burn center. Such a proper assessment represents a daunting task because severe burn injuries are rare. Inaccurate estimates often result in unjustified and costly transfers and unneeded fluid resuscitation and assisted ventilation procedures. Telemedicine offers a solution to these challenges. The present pilot study aims to investigate the feasibility, acceptability, and potential value of a large telemedicine initiative at the University of Montreal Health Center’s burn center and its network of referring hospitals.MethodsA three-stage study protocol is proposed to achieve this objective. First, a proof of concept phase will assess the technical feasibility of telemedicine at one referring hospital with a high volume of patient transfers. Second, the organizational and human feasibility of the project will be evaluated in four referring medical centers. All teleconsultation sessions will be analyzed using the WHO’s telemedicine implementation model. The third phase will consist of evaluating the potential impacts of telemedicine in a subset of 10 referring hospitals. The quality of communications between referring physicians and specialists will be assessed using semi-structured interviews. A pre-test/post-test with a comparison group design will be used to assess the effects of telemedicine on patient transfers, ventilation procedures, patient complications, mortality, length of ICU stay, and additional surgical procedures. The economic viability of telemedicine will be assessed using a cost-minimization approach.DiscussionThe telemedicine initiative is expected to yield positive and significant outcomes that are relevant to a wide range of medical centers that already use or are considering using a similar technology. The contribution of this pilot study lies in its ability to reveal technological, organizational, and human barriers and provide a preliminary assessment of the clinical and economic value of a large-scale telemedicine initiative in the context of burn medicine.

A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.

Luminescence Characteristics of Hybridized Polyfluorene

This study was to investigate luminescence characteristics of polyfluorene (PF) hybridized with silicone (agar sample) in term of the potential application in optoelectronic. The hybridization was accomplished by preparing silicone mixture comprising of epoxy and resin into different quantities (0.625 mg, 1.25 mg, 2.5 mg) of poly [(9, 9-dioctyl-fluorenyl-2, 7-diyl)-co-(1, 4-phenylene)] end capped with dimethylphenyl dissolved in toluene solution, followed by heating at 40℃ and stirring process for 5 min. In a proof of concept phase, luminescence properties of the hybridized samples were examined by using spectroscopic techniques UV-Visible (UV-VIS), photoluminescence (PL) and electroluminescence (EL). Changes in term of the peak intensity happened with respect to the quantities of PF being hybridized. Corresponding results have been systematically presented and discussed in this work.

Socio-demographic factors associated with quality of life after a multicomponent aphasia group therapy in people with sub-acute and chronic post-stroke aphasia

ABSTRACT Background: Group therapy has shown benefit in language recovery in patients with aphasia (PWA). However, many in the field question its role in improving quality of life for PWA, as well as whether socio-demographic factors are related to observed improvements. Aims: To explore socio-demographic characteristics potentially associated with improvement in quality of life following a multicomponent aphasia group therapy program in people with sub-acute and chronic stroke-related aphasia. Methods and procedures: This proof of concept Phase I pre- and post-test study investigated outcomes from 26 PWA more than 3 months after their first ischemic stroke following a multicomponent group therapy program. Each therapeutic group consisted of 5 to 6 participants, with a therapy intensity of 90 min twice a week for 12 weeks, and a total dose of 36 h. The primary outcome was the Stroke and Aphasia Quality of Life scale (SAQOL-39). The Boston Diagnostic Aphasia Examination Short Form (BDAE-SF) was used to evaluate potential changes in communication after therapy. Socio-demographic factors were analysed with respect to post-group SAQOL-39 scores. Outcomes and Results: A total of 26 patients participated in at least 80% of the therapy program, 65.4% male, mean age 59.2 years and a median post-stroke time of 8 months. Only the SAQOL-39 communication domain showed a significant increase after therapy (from 2.89 to 3.47; p = 0.016). There was a significant improvement in all aspects of the BDAE-SF after the group therapy. Being younger, having a caregiver, a larger number of people in the household, and being female were related to a greater gain in the SAQOL-39 communication domain. Younger PWA and milder aphasia severity were related to higher mean psychological domain scores after therapy. Conclusions and Implications: Multicomponent aphasia group therapy for PWA more than 3 months post-stroke may contribute to improving communication-related quality of life. Socio-demographic and stroke-related factors may be associated with a better therapeutic response. Future research should investigate the efficacy of this group therapy in a controlled trial, and the utility of treatment response predictors.

Variable High Precision Wide D-Band Phase Shifter

This paper proposes a new concept of designing compact high precision millimeter-wave wideband variable phase shifters. The phase shifter is implemented with a stacked shim with extremely short length of 0.9 mm and two waveguide flange adaptors with length of 0.5 mm. High precision phase shifting is achieved over entire D-band (110-170 GHz) by rotating the shim 90 degrees from aligned to perpendicular with consistent impedance matching performance. In addition, a glide-symmetric holey electromagnetic bandgap (EBG) structure is adopted to avoid wave leakage from the gap between the shim and the flange adaptors. A proof-of-concept (PoC) demonstrator is designed, manufactured, and tested. The measured results show that the designed stacked shim phase shifter with embedded EBG structure ensures return loss higher than 10 dB across 110-170 GHz with a 75 mu m airgap between waveguide flanges. The studied phase shifter provides a 0.88ffi phase shifting with each degree of mechanical rotation. The fabricated PoC phase shifter has a worst-case insertion loss of 0.92 dB and a return loss of 20 dB across the entire 110-170 GHz band and a maximum phase shift of 30 degrees. At 10 degrees phase shifting, the measured insertion loss is lower than 0.52 dB, and return loss is higher than 23 dB, respectively.

459P - Proof of concept clinical study by US-guided intratumor injection of VCN-01, an oncolytic adenovirus expressing hyaluronidase in patients with pancreatic cancer

459P - Proof of concept clinical study by US-guided intratumor injection of VCN-01, an oncolytic adenovirus expressing hyaluronidase in patients with pancreatic cancer

Abstract TP104: Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: Results of the Randomized Controlled PhaseII TEA-Stroke Trial

Introduction: In acute ischemic stroke, delayed revascularisation increases the risk of enlargement of the ischemic core associated with poor clinical outcome. Neuroprotective agents may immediately protect the penumbra and by that extend the time window for tissue-saving reperfusion. The vasoactive agent theophylline has been shown to reduce brain tissue edema, brain damage and mortality in animal stroke models. However, results from the animal studies, clinical case series and previous randomized clinical trials with theophylline in stroke patients were controversial. In this prospective trial, the primary study objective was to evaluate whether theophylline is safe and efficient in acute ischemic stroke patients as an add-on to thrombolytic therapy. Hypothesis: We hypothesized that treatment with theophylline can improve capillary flow in acute ischemic brain tissue and thus facilitate reperfusion leading to reduced volume of infarct growth and clinical improvement. Methods: The TEA-Stroke Trial is a two-center, proof of concept phase II clinical study with a randomized, double-blinded, placebo-controlled design. Patients with acute ischemic stroke verified by magnetic resonance imaging (MRI) and a National Institute of Health Stroke Scale ≥4 were randomized 1:1 to either theophylline or placebo as an add-on to standard thrombolytic therapy. The dual primary outcome measures included infarct growth assessed by MRI and clinical improvement assessed by the National Institute of Health Stroke scale at the 24-hour follow-up. A sample size of 120 subjects was estimated to detect a 22% difference between the treatment groups (80% power, alpha = 0.05) based on the MRI surrogate marker. Results: The study was stopped early after randomization of 64 patients for futility reasons because of slow recruitment. There were no safety concerns. Detailed blinded data analysis is ongoing and the main results will be presented. Conclusion: The TEA-Stroke Trial is the first study to evaluate whether the addition of theophylline to thrombolytic therapy is safe and efficient in patients with acute ischemic stroke. The main trial results will be discussed. Trial Registration: EudraCT number 2013-001989-42

Proof-of concept phase I study of everolimus, letrozole and trastuzumab in hormone receptor-positive, HER2-positive/amplified or mutant metastatic breast cancer or other solid tumors: Evaluating synergy and overcoming resistance.

2583 Background: Preclinical models suggested synergistic antineoplastic activity of anti-estrogen therapy with HER2 and mTOR inhibitors. Methods: We designed a 3+3 dose escalation phase I study of the aromatase inhibitor letrozole 2.5mg PO daily, mTOR inhibitor everolimus 2.5-10mg PO daily and HER2 antibody trastuzumab 4-8mg loading dose followed by 2-4mg maintenance dose IV on day 1 of 21-day cycle in patients with hormone-receptor positive, HER2-positive/amplified or mutant advanced cancers (confirmed by immunohistochemistry and/or FISH and/or next-generation sequencing). The primary objectives were to determine maximum tolerated dose (MTD), dose limiting toxicities (DLT), overall safety and response. Results: A total of 18 patients (men, 1; women, 17; HER2 amplification, 14; HER2 mutation, 4; breast cancer, 15; ovarian cancer, 1; cervical cancer, 1; gastroesophageal junction cancer, 1), median age 56 years, median of 6 prior therapies (including letrozole [9] or other aromatase inhibitor [8]; everolimus [3]; trastuzumab [14] or other HER2 targeted therapy [1]) were enrolled in the planned 6 dose levels. The MTD has not been reached and grade 3 (G3) mucositis at the dose level 4 was the only DLT. Other G3 or G4 drug-related toxicities included G4 hyperglycemia in 1 patient, G3 hyperglycemia in 3 patients, G3 thrombocytopenia in 1 patient, G3 anemia in 1 patient and G3 headache in 1 patient. Of 18 patients, 3 (17%) had a partial response (all with heavily-pretreated breast cancer with HER2 amplification [2] or HER2A775_G776insYVMA mutation [1]), 11 (61%) stable disease (SD) including 7 (39%) patients with SD > 6 months (all with heavily-pretreated breast cancer), 3 (17%) progressed and 1 had pending evaluation. The median change in size of target lesions per RECIST 1.1. was -11% (-68% to +47%). Median progression-free survival was 9 months (95% CI 5.8-12.2). Conclusions: The combination of letrozole, everolimus and trastuzumab is well tolerated with encouraging activity in heavily-pretreated patients with HER2-amplified or mutant advanced breast cancer. Clinical trial information: NCT02152943.

Archexin, a novel AKT-1–specific inhibitor for the treatment of metastatic renal cancer: Preliminary phase I data.

550 Background: Archexin (RX-0201) is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of Archexin's effect on AKT-1 mRNA levels was examined in human renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 cells and resulted in decreased AKT-1 mRNA levels. Methods: The current study is a proof of concept phase Ib/2, multicenter, open label 2-stage study for subjects who progressed on at least 1 VEGF-targeted therapy. Stage 1 is an open-label, dose-escalation phase Ib study of Archexin administered in combination with everolimus. Archexin is administered by a 24 hour continuous intravenous infusion for 14 days followed by 7 days of rest. It is hypothesized that 250 mg/m2/day or a lower dose of Archexin will be identified as safe and well-tolerated when administered in combination with 10 mg of everolimus. The dose of Archexin identified in Stage 1 will be studied further in Stage 2 which is the randomized, open-label, 2-arm study of Archexin in combination with 10 mg of everolimus versus 10 mg of everolimus alone. Plasma concentrations were measured using a validated LC-MS/MS assay, and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Results: Five subjects with metastatic clear cell renal carcinoma received 125 mg/m2/day (n = 3) or 200 mg/m2/day (n = 2) of Archexin with 10 mg of everolimus administered daily. Two subjects have had stable disease for 160 and 257 days. The most frequently reported treatment related adverse events for the combination were thrombocytopenia, vomiting and fatigue; no dose limiting toxicities have been reported currently. At all dose levels post-infusion, Archexin plasma concentrations increased rapidly and quickly reached a virtual plateau. Upon cessation of infusion on Day 14, plasma concentrations declined rapidly. Conclusions: At the dose levels tested, Archexin, in combination with everolimus, appears to be well tolerated in patients with metastatic renal cancer. Dose escalation/modification is ongoing to determine the recommended phase II dose of Archexin to be studied further in Stage 2 (randomized) when combined with everolimus. Clinical trial information: NCT02089334.

Detection of bacterial metabolites for the discrimination of bacteria utilizing gold nanoparticle chemiresistor sensors

The current methods for detecting and diagnosing bacterial infections have limitations that put lives at risk and threaten to burden healthcare systems with antibiotic resistant strains. Within the field of diagnostics, efforts continue to focus on developing new tools that are fast, easy to use and accessible to resource poor settings. Chemiresistor sensors are amongst new technologies being investigated to meet present needs for diagnosing diseases. Potential advantages of the technology include its amenability to point of care diagnostics, inexpensive components and rapid response times. Here, we present work on utilizing gold nanoparticle chemiresistors for the rapid detection and discrimination of bacteria in liquid samples. The detection principle is based on the distinct metabolic differences associated with species specific bacterial growth. For our proof of concept phase, the supernatant of defined bacterial liquid broth cultures were used. Principal component analysis on data from an array of gold nanoparticle chemiresistors was able to discriminate the culture supernatants of four bacterial species (Escherichia coli, Bacillus subtilis, Staphylococcus epidermidis and Enterobacter aerogenes). With basic unoptimized sensors, the detection limit for E. coli was indicated to be below 3.7×106CFU/mL and detection was achieved within 6h from low inoculation levels (102CFU/mL). Results indicated for the first time that gold nanoparticle chemiresistors can successfully detect and discriminate bacteria indirectly from liquid samples. The outcome of this investigation is positive for the continued development of gold nanoparticle chemiresistors for a much needed point of care diagnostic tool for rapidly detecting bacteria.

A multicenter, open-label, proof of concept phase 1b/2 study to evaluate the safety and efficacy of RX-0201 in combination with everolimus to treat subjects with advanced renal cell carcinoma.

TPS4580 Background: RX-0201 is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of RX-0201-mediated effect on AKT-1 mRNA levels was examine...

E-mobile support for community-based dementia caregivers: A proof of concept phase 1.

E-mobile support for community-based dementia caregivers: A proof of concept phase 1.

Signing recognition and Cloud bring advances for inclusion

PurposeThe paper's aim is to focus on: two projects that investigated innovative assistive technology solutions for people who sign (uKinect) and people with print impairments (MyDocStore); and a second phase that aims to create working prototypes for commercialisation.Design/methodology/approachThe approach was, in part, determined by the funding stages. In proof of concept phase, the organisations explored possibilities, identified barriers and, through user testing and feedback, refined processes. Trials are set to continue in Phase 2, when both projects will extend and improve functionality. uKinect applies gesture recognition and Microsoft's Kinect to the communication needs of Makaton sign language users. MyDocStore uses Cloud, desktop and mobile‐based file management to facilitate transfer of text files, converted into the user's preferred format, between devices. Both employ user‐centred development.FindingsuKinect helped signing learners to improve the clarity of their signing, while its linking of signing with computer games encouraged non‐signing students to decide to learn. MyDocStore demonstrated the possibility of automatic conversions and identified the benefits of such a system.Practical implicationsuKinect will accommodate varying levels of signing ability. MyDocStore will enable educational establishments to provide a variety of alternative formats simultaneously.Social implicationsuKinect aims to aid the transition into independent living and employment for Makaton users with learning difficulties and autism. MyDocStore's emphasis on mobile technology, automated conversions and multi‐platforms will make print‐impaired learners more independent and productive.Originality/valueThe paper shows that both systems use easily available, existing technology to provide accessible solutions for the target communities.

Thymidylate synthase genotype specific dosing of capecitabine: Proof of concept phase I study.

2551 Background: Thymidylate synthase (TYMS) is the target of fluoropyrimidines (FP). TYMS 3R3R is the predominant genotype in East Asian (EA) patients and is associated with increased TYMS expression, reduced FP related toxicity and relative FP resistance. Dose finding studies for FP were developed in Caucasians, a population that typically harbors TYMS 2R2R and 2R3R genotypes. We hypothesize the recommended phase II dose (RP2D) of capecitabine is higher in 3R3R and similar for 2R allele carriers compared to the FDA approved dose. Objectives 1) To determine the maximal tolerated dose (MTD) and RP2D of capecitabine in EA patients with advanced stage malignancy 2) To determine the safety and toxicity of this regimen and 3) To perform plasma pharmacokinetics (PK) of capecitabine and its metabolites. Methods: EA patients with advanced stage cancer were prospectively allocated into two cohorts: Group A (3R3R) and Group B (2R3R, 2R2R). In each cohort, dose escalation followed a standard phase I 3+3 design. Additional patients were treated at the R2P2 dose level (DL). Initial dose was 1250/m2 bd for 14 days q3w (DL 1) with 125 mg/m2 bd increments subsequently. Pharmacokinetics (PK) of capecitabine and its metabolites were performed using a LC-MS/MS method. Results: 23 patients (Group A=18; group B=5) received 94 cycles (median 2.5, range 1-8). Median age was 58 (range 34-74) years. Median turnaround time for TYMS genotyping was 1 day. In group A, grade 3-4 DLTs were seen in 3 patients: diarhoea, neutropenic fever, hand-foot syndrome, and mucositis. MTD was at DL 4 (1625mg/m2 bd) and the RP2D was 1500mg/m2 bd (DL 3). DL 3 was expanded to n=9. At DL 3, day 1 mean (± SD) capecitabine and 5FU Cmax was 12.3 ± 9.9 and 0.91 ± 0.73 µg/mL, respectively and AUC0 – t was 9.84 ± 5.53 and 1.21 ± 0.54 h*µg/mL, respectively. Compared with DL1, Cmax for capecitabine and 5FU was 2 and 2.02 fold higher and AUC 0-t was 1.49 and 1.59 fold higher at DL3. Accrual in group B was ceased at DL2 due to lack of patient enrolment; no DLT was seen. By ROC analysis, day 1 5FU AUC0 – t of 1.74 h*µg/mL predicted for DLT (p=0.022, sensitivity 100%, specificity 90%). Conclusions: In EA patients with TSER 3R3R, the RP2D was 1500 mg/m2 bd. The D1 5FU AUC0 – t at RP2D was 59% more than the FDA approved dose (DL1).

Applying a New Model for Sharing Population Health Data to National Syndromic Influenza Surveillance: DiSTRIBuTE Project Proof of Concept, 2006 to 2009

The Distributed Surveillance Taskforce for Real-time Influenza Burden Tracking and Evaluation (DiSTRIBuTE) project began as a pilot effort initiated by the International Society for Disease Surveillance (ISDS) in autumn 2006 to create a collaborative electronic emergency department (ED) syndromic influenza-like illness (ILI) surveillance network based on existing state and local systems and expertise. DiSTRIBuTE brought together health departments that were interested in: 1) sharing aggregate level data; 2) maintaining jurisdictional control; 3) minimizing barriers to participation; and 4) leveraging the flexibility of local systems to create a dynamic and collaborative surveillance network. This approach was in contrast to the prevailing paradigm for surveillance where record level information was collected, stored and analyzed centrally. The DiSTRIBuTE project was created with a distributed design, where individual level data remained local and only summarized, stratified counts were reported centrally, thus minimizing privacy risks. The project was responsive to federal mandates to improve integration of federal, state, and local biosurveillance capabilities. During the proof of concept phase, 2006 to 2009, ten jurisdictions from across North America sent ISDS on a daily to weekly basis year-round, aggregated data by day, stratified by local ILI syndrome, age-group and region. During this period, data from participating U.S. state or local health departments captured over 13% of all ED visits nationwide. The initiative focused on state and local health department trust, expertise, and control. Morbidity trends observed in DiSTRIBuTE were highly correlated with other influenza surveillance measures. With the emergence of novel A/H1N1 influenza in the spring of 2009, the project was used to support information sharing and ad hoc querying at the state and local level. In the fall of 2009, through a broadly collaborative effort, the project was expanded to enhance electronic ED surveillance nationwide.

Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration

There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.

A proof-of-concept (PoC) phase II criterion in a noninferiority context with application in patients with metastatic renal cell carcinoma (mRCC).

e15055 Background: Single arm phase II studies provide limited information with respect to the efficacy of new treatments. A randomized phase II study using PFS as endpoint allows a more reliable PoC for further development of the new treatment in phase III. A PoC phase II design is proposed to establish the non-inferiority of a new treatment compared to a control treatment. Methods: A Bayesian PoC phase II design is proposed with the objective to have (1) a reasonably promising effect (treatment vs. control) estimate, and (2) good evidence that the treatment is better than a predefined non-inferiority margin. For (1) clinical input is required in order to implement an explicit rejection bound for the estimated effect, e.g. the maximum observed hazard ratio (HR) which could be still considered as similar to 1 (HR=1 means no treatment difference). The design is applied in the RECORD-3 (Renal cell cancer treatment with oral RAD001 given Daily) trial comparing the treatment sequence everolimus

4Ps Framework of Tooling Development and Management

4Ps (Proof of concept, Product development, Production, Product Retirement) framework of tooling development and management processes has been established to improve tooling design and manufacture workflow, communication, quality, OTD(On-Time Delivery). A creation of a scalable and flexible best-of-breed workflow from proof of concept phase to production retirement phase has been introduced and strongly supported the needs of each development team of tooling project. The creation and standardization of 4Ps framework have clearly identified and explored the activities, responsibilities and deliverables of tooling project team, throughout the tooling life cycle. Some toolmakers of famous IT companies have benefited considerably by applying these processes.