857 resultados para Phase-ii Trial


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We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC. © 2012 Elsevier Inc. All Rights Reserved.

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Aim: To examine if fasting affects serum bilirubin levels in clinical healthy males and females. Methods: We utilised retrospective data from phase 1 clinical trials where blood was collected in either a fed or fasting state at screening and pre-dosing time points and analysed for total bilirubin levels as per standard clinical procedures. Participants were clinically healthy males (n = 105) or females (n = 30) aged 18 to 48 inclusive who participated in a phase 1 clinical trial in 2012 or 2013. Results: We found a statistically significant increase in total serum bilirubin levels in fasting males as compared to non-fasting males. The fasting time correlated positively with increased bilirubin levels. The age of the healthy males did not correlate with their fasting bilirubin level. We found no correlation between fasting and bilirubin levels in clinically normal females. Conclusions: The recruitment and screening of volunteers for a clinical trial is a time-consuming and expensive process. This study clearly demonstrates that testing for serum bilirubin should be conducted on non-fasting male subjects. If fasting is required, then participants should not be excluded from a trial based on an elevated serum bilirubin that is deemed non-clinically significant.

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Purpose To investigate the effects of a natural oil-based emulsion containing allantoin versus aqueous cream for preventing and managing radiation induced skin reactions (RISR). Methods and Materials A total of 174 patients were randomised and participated in the study. Patients either received Cream 1 (the natural oil-based emulsion containing allantoin) or Cream 2 (aqueous cream). Skin toxicity, pain, itching and skin-related quality of life scores were collected for up to four weeks after radiation treatment. Results Patients who received Cream 1 had a significantly lower average level of Common Toxicity Criteria at week 3 (p<0.05), but had statistically higher average levels of skin toxicity at weeks 7, 8 and 9 (all p<0.001). Similar results were observed when skin toxicity was analysed by grades. With regards to pain, patients in the Cream 2 group had a significantly higher average level of worst pain (p<0.05) and itching (p=0.046) compared to the Cream 1 group at week 3, however these differences were not observed at other weeks. In addition, there was a strong trend for Cream 2 to reduce the incidence of grade 2 or more skin toxicity in comparison to Cream 1 (p=0.056). Overall, more participants in the Cream 1 group were required to use another topical treatment at weeks 8 (p=0.049) and 9 (p=0.01). Conclusion The natural oil-based emulsion containing allantoin appears to have similar effects for managing skin toxicity compared to aqueous cream up to week 5, however, it becomes significantly less effective at later weeks into the radiation treatment and beyond treatment completion (week 6 and beyond). There were no major differences in pain, itching and skin-related quality of life. In light of these results, clinicians and patients can base their decision on costs and preferences. Overall, aqueous cream appears to be a more preferred option.

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The oxidation of aqueous sulfur dioxide in the presence of polymer-supported copper(II) catalyst is also accompanied by homogeneous oxidation of aqueous sulfur dioxide catalyzed by leached copper(II) ions. Aqueous phase oxidation of sulfur dioxide of low concentrations by oxygen in the presence of dissolved copper(II) has therefore been studied. The solubility of SO2 in aqueous solutions is not affected by the concentration of copper(II) in the solution. In the oxidation reaction, only HSO3- is the reactive S(IV) species. Based on this observation a rate model which also incorporates the effect of sulfuric acid on the solubility of SO2 is developed. The rate model includes a power-law type term for the rate of homogeneous phase reaction obtained from a proposed free-radical chain mechanism for the oxidation. Experiments are conducted at various levels of concentrations of SO2 and O-2 in the gas phase and Cu(II) in the liquid phase. The observed orders are one in each of O-2, Cu(II) and HSO3-. This suggests a first-order termination of the free radicals of bisulfite ions.

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A general theory is evolved for a class of macrogrowth models which possess two independent growth-rates. Relations connecting growth-rates to growth geometry are established and some new growth forms are shown to result for models with passivation or diffusion-controlled rates. The corresponding potentiostatic responses, their small and large time behaviours and peak characteristics are obtained. Numerical transients are also presented. An empirical equation is derived as a special case and an earlier equation is corrected. An interesting stochastic result pertaining to nucleation events in the successive layers is proved.

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The Gibbs' energy change for the reaction, 3CoO (r.s.)+1/2O2(g)→Co3O4(sp), has been measured between 730 and 1250 K using a solid state galvanic cell: Pt, CuO+Cu2O|(CaO)ZrO2|CoO+Co3O4,Pt. The emf of this cell varies nonlinearly with temperature between 1075 and 1150 K, indicating a second or higher order phase transition in Co3O4around 1120 (±20) K, associated with an entropy change of ∼43 Jmol-1K-1. The phase transition is accompanied by an anomalous increase in lattice parameter and electrical conductivity. The cubic spinel structure is retained during the transition, which is caused by the change in CO+3 ions from low spin to high spin state. The octahedral site preference energy of CO+3 ion in the high spin state has been evaluated as -24.8 kJ mol-1. This is more positive than the value for CO+2 ion (-32.9 kJ mol-1). The cation distribution therefore changes from normal to inverse side during the phase transition. The transformation is unique, coupling spin unpairing in CO+3 ion with cation rearrangement on the spinel lattice, DTA in pure oxygen revealed a small peak corresponding to the transition, which could be differentiated from the large peak due to decomposition. TGA showed that the stoichiometry of oxide is not significantly altered during the transition. The Gibbs' energy of formation of Co3O4 from CoO and O2 below and above phase transition can be represented by the equations:ΔG0=-205,685+170.79T(±200) J mol-1(730-1080 K) and ΔG0=-157,235+127.53T(±200) J mol-1(1150-1250 K).

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Wet chemical reaction of hydrated alumina gels, Al2O3.yH(2)O(80

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Aqueous phase oxidation of sulphur dioxide at low concentrations catalysed by a PVP-Cu complex in the solid phase and dissolved Cu(II) in the liquid phase is studied in a rotating catalyst basket reactor (RCBR). The equilibrium adsorption of Cu(II) and S(VI) on PVP particles is found to be of the Langmuir-type. The diffusional effects of S(IV) species in PVP-Cu resin are found to be insignificant whereas that of product S(VI) are found to be significant. The intraparticle diffusivity of S(VI) is obtained from independent tracer experiments. In the oxidation reaction HSO3- is the reactive species. Both the S(IV) species in the solution, namely SO2(aq) and HSO3- get adsorbed onto the active PVP-Cu sites of the catalyst, but only HSO3- undergoes oxidation. A kinetic mechanism is proposed based on this feature which shows that SO2(aq) has a deactivating effect on the catalyst. A rate model is developed for the three-phase reaction system incorporating these factors along with the effect of concentration of H2SO4 on the solubility of SO2 in the dilute aqueous solutions of Cu(II). Transient oxidation experiments are conducted at different conditions of concentration of SO2 and O-2 in the gas phase and catalyst concentration, and the rate parameters are estimated from the data. The observed and calculated profiles are in very good agreement. This confirms the deactivating effect of nonreactive SO2(aq) on the heterogeneous catalysis.

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Internal vibration modes of bis-(alkylammonium) tetrachlorometallates(II) and the corresponding alkylammonium chlorides have been studied through their phase transitions using infrared spectroscopy. The studies show that the vibrational states of alkylammonium ions change markedly through the phase transitions. Spectra of the analogous tetrabromometallates and alkylammonium bromides also confirm this behaviour. There is appreciable motion of the alkylammonium ions in the high-temperature phases; thus, CH3NH+3 ions are essentially undistorted in these phases. The low-temperature, ordered phases show evidence of stronger hydrogen bonding of the cations and for the presence of C—N torsional modes.

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Objectives:To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity.Design:This was a pilot, open-label, three-arm prospective phase 1 study.Methods:We recruited 28 patients with low plasma vitamin D (<50nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200000IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4(+) T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation.Results:One month of vitamin D supplementation restored plasma levels to sufficiency (>75nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1 - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced.Conclusion:Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

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The phase behavior of liquid crystalline in the ternary system of dodecyl dimethyl ammonium hydroxyl propyl sulfonate(DDAHPS)/1-pentanol(C5H11OH)/water deuteron (D2O) has been investigated by polarizing optical microscopy, H-2 NMR spectroscopy methods. The results indicate that two kinds of liquid crystals (the lamellar, and the hexagonal) exist in the liquid crystalline phase region. In this paper, we also use the polarized Raman spectroscopy method to measure the values of the order/disorder parameters and the values of the environment polarity parameters for the samples selected from the liquid crystalline phase region, and compare these two parameters of the samples with those of solid state DDAHPS and liquid state pentan-1-ol.

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Part I.

We have developed a technique for measuring the depth time history of rigid body penetration into brittle materials (hard rocks and concretes) under a deceleration of ~ 105 g. The technique includes bar-coded projectile, sabot-projectile separation, detection and recording systems. Because the technique can give very dense data on penetration depth time history, penetration velocity can be deduced. Error analysis shows that the technique has a small intrinsic error of ~ 3-4 % in time during penetration, and 0.3 to 0.7 mm in penetration depth. A series of 4140 steel projectile penetration into G-mixture mortar targets have been conducted using the Caltech 40 mm gas/ powder gun in the velocity range of 100 to 500 m/s.

We report, for the first time, the whole depth-time history of rigid body penetration into brittle materials (the G-mixture mortar) under 105 g deceleration. Based on the experimental results, including penetration depth time history, damage of recovered target and projectile materials and theoretical analysis, we find:

1. Target materials are damaged via compacting in the region in front of a projectile and via brittle radial and lateral crack propagation in the region surrounding the penetration path. The results suggest that expected cracks in front of penetrators may be stopped by a comminuted region that is induced by wave propagation. Aggregate erosion on the projectile lateral surface is < 20% of the final penetration depth. This result suggests that the effect of lateral friction on the penetration process can be ignored.

2. Final penetration depth, Pmax, is linearly scaled with initial projectile energy per unit cross-section area, es , when targets are intact after impact. Based on the experimental data on the mortar targets, the relation is Pmax(mm) 1.15es (J/mm2 ) + 16.39.

3. Estimation of the energy needed to create an unit penetration volume suggests that the average pressure acting on the target material during penetration is ~ 10 to 20 times higher than the unconfined strength of target materials under quasi-static loading, and 3 to 4 times higher than the possible highest pressure due to friction and material strength and its rate dependence. In addition, the experimental data show that the interaction between cracks and the target free surface significantly affects the penetration process.

4. Based on the fact that the penetration duration, tmax, increases slowly with es and does not depend on projectile radius approximately, the dependence of tmax on projectile length is suggested to be described by tmax(μs) = 2.08es (J/mm2 + 349.0 x m/(πR2), in which m is the projectile mass in grams and R is the projectile radius in mm. The prediction from this relation is in reasonable agreement with the experimental data for different projectile lengths.

5. Deduced penetration velocity time histories suggest that whole penetration history is divided into three stages: (1) An initial stage in which the projectile velocity change is small due to very small contact area between the projectile and target materials; (2) A steady penetration stage in which projectile velocity continues to decrease smoothly; (3) A penetration stop stage in which projectile deceleration jumps up when velocities are close to a critical value of ~ 35 m/s.

6. Deduced averaged deceleration, a, in the steady penetration stage for projectiles with same dimensions is found to be a(g) = 192.4v + 1.89 x 104, where v is initial projectile velocity in m/s. The average pressure acting on target materials during penetration is estimated to be very comparable to shock wave pressure.

7. A similarity of penetration process is found to be described by a relation between normalized penetration depth, P/Pmax, and normalized penetration time, t/tmax, as P/Pmax = f(t/tmax, where f is a function of t/tmax. After f(t/tmax is determined using experimental data for projectiles with 150 mm length, the penetration depth time history for projectiles with 100 mm length predicted by this relation is in good agreement with experimental data. This similarity also predicts that average deceleration increases with decreasing projectile length, that is verified by the experimental data.

8. Based on the penetration process analysis and the present data, a first principle model for rigid body penetration is suggested. The model incorporates the models for contact area between projectile and target materials, friction coefficient, penetration stop criterion, and normal stress on the projectile surface. The most important assumptions used in the model are: (1) The penetration process can be treated as a series of impact events, therefore, pressure normal to projectile surface is estimated using the Hugoniot relation of target material; (2) The necessary condition for penetration is that the pressure acting on target materials is not lower than the Hugoniot elastic limit; (3) The friction force on projectile lateral surface can be ignored due to cavitation during penetration. All the parameters involved in the model are determined based on independent experimental data. The penetration depth time histories predicted from the model are in good agreement with the experimental data.

9. Based on planar impact and previous quasi-static experimental data, the strain rate dependence of the mortar compressive strength is described by σf0f = exp(0.0905(log(έ/έ_0) 1.14, in the strain rate range of 10-7/s to 103/s (σ0f and έ are reference compressive strength and strain rate, respectively). The non-dispersive Hugoniot elastic wave in the G-mixture has an amplitude of ~ 0.14 GPa and a velocity of ~ 4.3 km/s.

Part II.

Stress wave profiles in vitreous GeO2 were measured using piezoresistance gauges in the pressure range of 5 to 18 GPa under planar plate and spherical projectile impact. Experimental data show that the response of vitreous GeO2 to planar shock loading can be divided into three stages: (1) A ramp elastic precursor has peak amplitude of 4 GPa and peak particle velocity of 333 m/s. Wave velocity decreases from initial longitudinal elastic wave velocity of 3.5 km/s to 2.9 km/s at 4 GPa; (2) A ramp wave with amplitude of 2.11 GPa follows the precursor when peak loading pressure is 8.4 GPa. Wave velocity drops to the value below bulk wave velocity in this stage; (3) A shock wave achieving final shock state forms when peak pressure is > 6 GPa. The Hugoniot relation is D = 0.917 + 1.711u (km/s) using present data and the data of Jackson and Ahrens [1979] when shock wave pressure is between 6 and 40 GPa for ρ0 = 3.655 gj cm3 . Based on the present data, the phase change from 4-fold to 6-fold coordination of Ge+4 with O-2 in vitreous GeO2 occurs in the pressure range of 4 to 15 ± 1 GPa under planar shock loading. Comparison of the shock loading data for fused SiO2 to that on vitreous GeO2 demonstrates that transformation to the rutile structure in both media are similar. The Hugoniots of vitreous GeO2 and fused SiO2 are found to coincide approximately if pressure in fused SiO2 is scaled by the ratio of fused SiO2to vitreous GeO2 density. This result, as well as the same structure, provides the basis for considering vitreous Ge02 as an analogous material to fused SiO2 under shock loading. Experimental results from the spherical projectile impact demonstrate: (1) The supported elastic shock in fused SiO2 decays less rapidly than a linear elastic wave when elastic wave stress amplitude is higher than 4 GPa. The supported elastic shock in vitreous GeO2 decays faster than a linear elastic wave; (2) In vitreous GeO2 , unsupported shock waves decays with peak pressure in the phase transition range (4-15 GPa) with propagation distance, x, as α 1/x-3.35 , close to the prediction of Chen et al. [1998]. Based on a simple analysis on spherical wave propagation, we find that the different decay rates of a spherical elastic wave in fused SiO2 and vitreous GeO2 is predictable on the base of the compressibility variation with stress under one-dimensional strain condition in the two materials.

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In the first part I perform Hartree-Fock calculations to show that quantum dots (i.e., two-dimensional systems of up to twenty interacting electrons in an external parabolic potential) undergo a gradual transition to a spin-polarized Wigner crystal with increasing magnetic field strength. The phase diagram and ground state energies have been determined. I tried to improve the ground state of the Wigner crystal by introducing a Jastrow ansatz for the wave function and performing a variational Monte Carlo calculation. The existence of so called magic numbers was also investigated. Finally, I also calculated the heat capacity associated with the rotational degree of freedom of deformed many-body states and suggest an experimental method to detect Wigner crystals.

The second part of the thesis investigates infinite nuclear matter on a cubic lattice. The exact thermal formalism describes nucleons with a Hamiltonian that accommodates on-site and next-neighbor parts of the central, spin-exchange and isospin-exchange interaction. Using auxiliary field Monte Carlo methods, I show that energy and basic saturation properties of nuclear matter can be reproduced. A first order phase transition from an uncorrelated Fermi gas to a clustered system is observed by computing mechanical and thermodynamical quantities such as compressibility, heat capacity, entropy and grand potential. The structure of the clusters is investigated with the help two-body correlations. I compare symmetry energy and first sound velocities with literature and find reasonable agreement. I also calculate the energy of pure neutron matter and search for a similar phase transition, but the survey is restricted by the infamous Monte Carlo sign problem. Also, a regularization scheme to extract potential parameters from scattering lengths and effective ranges is investigated.

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Part I

A study of the thermal reaction of water vapor and parts-per-million concentrations of nitrogen dioxide was carried out at ambient temperature and at atmospheric pressure. Nitric oxide and nitric acid vapor were the principal products. The initial rate of disappearance of nitrogen dioxide was first order with respect to water vapor and second order with respect to nitrogen dioxide. An initial third-order rate constant of 5.5 (± 0.29) x 104 liter2 mole-2 sec-1 was found at 25˚C. The rate of reaction decreased with increasing temperature. In the temperature range of 25˚C to 50˚C, an activation energy of -978 (± 20) calories was found.

The reaction did not go to completion. From measurements as the reaction approached equilibrium, the free energy of nitric acid vapor was calculated. This value was -18.58 (± 0.04) kilocalories at 25˚C.

The initial rate of reaction was unaffected by the presence of oxygen and was retarded by the presence of nitric oxide. There were no appreciable effects due to the surface of the reactor. Nitric oxide and nitrogen dioxide were monitored by gas chromatography during the reaction.

Part II

The air oxidation of nitric oxide, and the oxidation of nitric oxide in the presence of water vapor, were studied in a glass reactor at ambient temperatures and at atmospheric pressure. The concentration of nitric oxide was less than 100 parts-per-million. The concentration of nitrogen dioxide was monitored by gas chromatography during the reaction.

For the dry oxidation, the third-order rate constant was 1.46 (± 0.03) x 104 liter2 mole-2 sec-1 at 25˚C. The activation energy, obtained from measurements between 25˚C and 50˚C, was -1.197 (±0.02) kilocalories.

The presence of water vapor during the oxidation caused the formation of nitrous acid vapor when nitric oxide, nitrogen dioxide and water vapor combined. By measuring the difference between the concentrations of nitrogen dioxide during the wet and dry oxidations, the rate of formation of nitrous acid vapor was found. The third-order rate constant for the formation of nitrous acid vapor was equal to 1.5 (± 0.5) x 105 liter2 mole-2 sec-1 at 40˚C. The reaction rate did not change measurably when the temperature was increased to 50˚C. The formation of nitric acid vapor was prevented by keeping the concentration of nitrogen dioxide low.

Surface effects were appreciable for the wet tests. Below 35˚C, the rate of appearance of nitrogen dioxide increased with increasing surface. Above 40˚C, the effect of surface was small.

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Part I:

The perturbation technique developed by Rannie and Marble is used to study the effect of droplet solidification upon two-phase flow in a rocket nozzle. It is shown that under certain conditions an equilibrium flow exists, where the gas and particle phases have the same velocity and temperature at each section of the nozzle. The flow is divided into three regions: the first region, where the particles are all in the form of liquid droplets; a second region, over which the droplets solidify at constant freezing temperature; and a third region, where the particles are all solid. By a perturbation about the equilibrium flow, a solution is obtained for small particle slip velocities using the Stokes drag law and the corresponding approximation for heat transfer between the particle and gas phases. Singular perturbation procedure is required to handle the problem at points where solidification first starts and where it is complete. The effects of solidification are noticeable.

Part II:

When a liquid surface, in contact with only its pure vapor, is not in the thermodynamic equilibrium with it, a net condensation or evaporation of fluid occurs. This phenomenon is studied from a kinetic theory viewpoint by means of moment method developed by Lees. The evaporation-condensation rate is calculated for a spherical droplet and for a liquid sheet, when the temperatures and pressures are not too far removed from their equilibrium values. The solutions are valid for the whole range of Knudsen numbers from the free molecule to the continuum limit. In the continuum limit, the mass flux rate is proportional to the pressure difference alone.