The practical application of adaptive study design in early phase clinical trials: a retrospective analysis of time savings.

BACKGROUND: The interest in adaptive study design is evident from the growing amount of clinical research employing this model in the mid to later stages of medicines development. Little has been published on the practical application and merits of adaptive study design in early phase clinical research. METHODS: This paper describes a retrospective analysis performed on a sample of 29 industry lead adaptive early phase studies commencing between 1 January 2006 and 31 December 2010 in a clinical trials unit in London, England. All studies containing at least one adaptive feature in the original protocol were included in the analysis. The scope of the analysis was to assess whether the use of adaptive study designs provided tangible benefits over the use of conventional study designs using time savings as the main measure. CONCLUSION: We conclude that the use of adaptive study design saves time in early phase research programs. This is achieved by abolishing the need for substantial amendments or by mitigating their impact on timelines and by using adaptive scheduling efficiencies.

Cardiac Safety of Rupatadine in a Single-Ascending-Dose and Multiple-Ascending-Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments-Comparison With the Previous White Caucasian Thorough QT Study.

A thorough QT/QTc study in healthy white Caucasian subjects demonstrated that rupatadine has no proarrhythmic potential and raised no cardiac safety concerns. The present phase 1 study aimed to confirm the cardiac safety of rupatadine in healthy Japanese subjects. In this randomized, double-blind, placebo-controlled study, 27 healthy Japanese subjects were administered single and multiple escalating rupatadine doses of 10, 20, and 40 mg or placebo. Triplicate electrocardiogram (ECG) recordings were performed on days -1, 1, and 5 at several points, and time-matched pharmacokinetic samples were also collected. Concentration-effect analysis based on the change in the QT interval corrected using Fridericia's formula (QTcF) from average baseline was performed. Data from the formal TQT study in white Caucasian subjects was used for a comparison analysis. The ECG data for rupatadine at doses up to 40 mg did not show an effect on the QTc interval of regulatory concern. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a significant shortening of QTcF on days 1 and 5 four hours after a standardized meal. The data from this study exhibited no statistically significant differences in the QTc effect between Japanese and white Caucasian subjects.

Real-time measurement of radiation exposure to patients during diagnostic coronary angiography and percutaneous interventional procedures.

OBJECTIVES: The aim of this study was to accurately assess the radiation exposure received by patients during cardiac catheterization in a large sample representative of the current state of practice in cardiac angiography. BACKGROUND: Radiation exposure to patients and laboratory staff has been recognized as a necessary hazard in coronary angiography. The effects on x-ray exposure of the increased complexity of coronary angiographic procedures and, in particular, the increasing use of coronary artery stenting, have not been adequately addressed in previous studies. METHODS: X-ray exposure measurements were performed on a consecutive series of 972 patients undergoing 992 diagnostic and interventional studies in the Mayo Clinic catheterization laboratory within an eight week period in late 1997. Data were acquired from 706 diagnostic procedures and 286 interventional procedures using a real-time exposure measurement system to continuously calculate and record the exposure rate and total exposure, reflecting all parameters relevant to the specific patient and procedure situation. RESULTS: The median exposure for all 992 procedures was 41.8 mC/kg (162.1 R); the corresponding values for diagnostic and interventional procedures were 34.9 and 95.6 mC/kg, respectively (135.3 vs. 370.5 R). There were significant differences in the fluoroscopy exposure time between diagnostic and interventional procedures: 4.7 min vs. 21.0 min. Heavier patients (>83 kg) received x-ray exposures at a significantly higher rate than did lighter patients (<83 kg) during both fluoroscopy and cine; 44.9 mC/kg/min (173.9 R/min) vs. 27.9 mC/kg/min (108.3 R/min) for cine exposure rate and 2.3 mC/kg/min (8.8 R/min) vs. 1.5 mC/kg/min (5.8 R/min) for fluoroscopy exposure rate. CONCLUSIONS: Changes in practice have led to higher values for patient x-ray radiation exposures during cardiac catheterization procedures. The real-time display and recording of x-ray exposure facilitates the reduction of exposure in the catheterization laboratory.

A comparison of simplified lansoprazole suspension administered nasogastrically and pantoprazole administered intravenously: effects on 24-h intragastric pH.

AIM: To compare the 24-h intragastric pH effects of simplified lansoprazole suspension, 30 mg, administered nasogastrically, with pantoprazole, 40 mg, administered intravenously. METHODS: Thirty-six healthy adults were enrolled and given simplified lansoprazole suspension, 30 mg (nasogastrically), or pantoprazole, 40 mg (intravenously), once daily for five consecutive days in a cross-over fashion. Intragastric pH was monitored at baseline and on Days 1 and 5 of each treatment period. The pharmacokinetic parameters of lansoprazole and pantoprazole were also determined on Days 1 and 5. RESULTS: No statistically significant changes in pharmacokinetic parameters occurred between Days 1 and 5 with either regimen, except for pantoprazole Cmax. On Days 1 and 5, significantly higher mean 24-h intragastric pH values were observed with 30 mg simplified lansoprazole suspension compared with 40 mg intravenous pantoprazole (Day 1, 3.13 vs. 2.67; Day 5, 3.95 vs. 3.61, respectively; P < 0.05). Additionally, 30 mg simplified lansoprazole suspension produced significantly (P < 0.05) higher percentages of time intragastric pH was above 3, 4, 5 or 6 as compared with 40 mg intravenous pantoprazole throughout Days 1 and 5. CONCLUSIONS: A 30 mg dose of simplified lansoprazole suspension administered nasogastrically was consistently more effective at controlling intragastric pH than pantoprazole, 40 mg, administered intravenously.

Cizolirtine citrate (E-4018) in the treatment of chronic neuropathic pain.

This study was performed to determine the efficacy and safety of oral cizolirtine citrate, a novel agent, in the treatment of chronic neuropathic pain. Cizolirtine was tested in a double-blind, placebo-controlled, two-way crossover study, having previously been shown to have significant analgesic and anti-hyperalgesic action in neuropathic pain models and preliminary human studies. Twenty-five patients with neuropathic pain, which was persistent for at least three months, and scored > 30 mm on a 100 mm visual analogue scale (VAS), were included. A subgroup of five patients had primary skin allodynia, i.e. pain evoked by non-noxious stimuli in the territory of the injured nerve. Cizolirtine 200 mg or placebo was administered twice daily for a treatment period of 21 days, each separated by a washout interval of 7 days. Assessments of skin allodynia were performed using the graded monofilaments (von Frey hairs) on days 1 (predose), 14 and 21 (90 min postdose). All patients were instructed to maintain a daily pain diary throughout the study. Results showed that the differences in VAS and allodynia scores between cizolirtine and placebo treatments were not significant in the overall analysis (p > or = 0.05); cizolirtine was well tolerated. In a subgroup of five patients with primary allodynia, a 53% reduction in VAS score from baseline at rest (p = 0.007) and 55% on movement (p = 0.0002) at day 21 was observed with cizolirtine, as compared to 8% at rest (p = 0.5215) and 13% on movement (p = 0.4187) with placebo. Similarly, allodynia improved with cizolirtine (p = 0.03) but not with placebo (p = 0.9) in this subgroup. Cizolirtine may be effective in primary allodynia after peripheral nerve injury, and a further trial in a larger number of such subjects is warranted.

Artefacts found in computed radiography.

Artefacts on radiographic images are distracting and may compromise accurate diagnosis. Although most artefacts that occur in conventional radiography have become familiar, computed radiography (CR) systems produce artefacts that differ from those found in conventional radiography. We have encountered a variety of artefacts in CR images that were produced from four different models plate reader. These artefacts have been identified and traced to the imaging plate, plate reader, image processing software or laser printer or to operator error. Understanding the potential sources of CR artefacts will aid in identifying and resolving problems quickly and help prevent future occurrences.

Comparison of ultrasound quality assurance phantom measurements from matched and mixed scanner-transducer combinations.

Our goal in this work was to compare the results of common phantom tests made using matched and mixed ultrasound (US) scanner-transducer combinations. Sets of common US quality assurance (QA) measurements were made using matched US scanner-transducer combinations (i.e., transducers purchased for use with a particular scanner), as well as unmatched (mixed) combinations. Measurements of vertical and horizontal distance accuracy, and depth of penetration were performed using three common transducer types. Means, standard deviations, and differences between the mean mix and match measurements divided by the standard deviation (match-mix difference, or MMD), and two-sided, paired t-tests were computed for the groups of mixed and matched measurements. MMDs for vertical and horizontal distance accuracy test results were less than 0.87 in all cases, well below our threshold value of 2.0, which indicates that a significant difference exists. MMDs for the depth of penetration measurements were less than 1.50, again below the threshold value. These results suggest that all of the mixed and matched data sets were very similar. The more sensitive t-tests indicate statistically significant differences in only 2 of the 18 pairs of data sets. In conclusion, this study suggests that QA measurements generated by mixed or matched scanner-transducer combinations are very comparable. The ability to obtain QA phantom test data from mixed scanner-transducer combinations reduces the time required for US QA testing.

The suppression of gastro-oesophageal reflux by alginates.

AIMS: The aim of this study was to compare alginate products with the same amount of active ingredients but different dosage forms, in the suppression of reflux provoked by a standard meal in healthy human volunteers, using ambulatory oesophageal pH monitoring. METHODS: This was a single centre, randomised, open, three-period crossover, controlled study comparing Gaviscon Advance (10 ml) with a control (10 ml water) and with a new tablet product containing the same active ingredients as Gaviscon Advance. Volunteers who had oesophageal pH < 4 for at least 2% of the 4-h period after ingestion of a test meal followed by control at a reflux screening visit were included in the study. RESULTS: The difference between Gaviscon Advance and control in the mean angular transformed percentage of time for which oesophageal pH fell below four was statistically significant (p < 0.0001) demonstrating the sensitivity of the method. No significant difference between the two alginate products was found based on the least squares adjusted mean angular transformed percentage of time for which pH fell below four. There were also no significant differences between the two alginate dosage forms in the angular transformed percentage of time for which oesophageal pH fell below five and in the log-transformed number of occasions on which oesophageal pH fell below four and five. DISCUSSION AND CONCLUSION: The study shows that alginate reflux suppressants containing a low amount of antacid are effective in suppressing acid reflux and that suspension and tablet forms are able to give equivalent acid suppression.

Effects of ionizing radiation and magnetic fields on digital data stored on floppy disks.

PURPOSE: To evaluate the effect of x rays and magnetic fields on high-density, 3.5-inch floppy disks. MATERIALS AND METHODS: A 1-Mbyte worksheet file was stored on 20 recently purchased high-density floppy disks. Five disks were stored as controls. Five other disks were then exposed to 70-kVp and 6-MV x rays with exposures of 100-1,000 R (0.026-0.26 C.kg-1). Ten other disks were exposed to magnetic fields with a maximum strength of 1,000 G. Magnetic fields around an airport metal detector and x-ray unit were measured. Another set of 10 disks was passed through the metal detector 50 times and through the x-ray unit 12 times. RESULTS: Ionizing radiation had no effect on the data stored on the disks. Magnetic fields with a maximum strength of 500 G had no effect, but field strengths of 1,000 G completely erased the data. Neither the airport metal detector nor the x-ray unit had any effect on the data. CONCLUSION: Airport metal detectors and x-ray scanners have no effect on digital data stored on floppy disks.

Quantitative evaluation of low-cost frame-grabber boards for personal computers.

Nine moderately priced frame-grabber boards for both Macintosh (Apple Computers, Cupertino, CA) and IBM-compatible computers were evaluated using a Society of Motion Pictures and Television Engineers (SMPTE) pattern and a video signal generator for dynamic range, gray-scale reproducibility, and spatial integrity of the captured image. The degradation of the video information ranged from minor to severe. Some boards are of reasonable quality for applications in diagnostic imaging and education. However, price and quality are not necessarily directly related.

Effects on 24-hour intragastric pH: a comparison of lansoprazole administered nasogastrically in apple juice and pantoprazole administered intravenously.

OBJECTIVE: To compare the 24-h intragastric pH effects of lansoprazole, 30 mg administered nasogastrically, with pantoprazole, 40 mg administered i.v. METHODS: Healthy adults were enrolled in an open label, two-way crossover, single-center study. Thirty milligrams of lansoprazole (administered nasogastrically in apple juice) or pantoprazole (i.v.) were administered once daily at 8:00 AM for 5 consecutive days with at least a 2-wk washout period between the regimens. Ambulatory 24-h intragastric pH was monitored at baseline and on days 1 and 5 of each treatment period. Blood specimens were collected on days I and 5 for pharmacokinetic parameter determinations. RESULTS: Thirty-three adults completed both crossover periods, with the exception of one patient with a zero lansoprazole plasma concentration on day 1 of period 2. Lansoprazole, 30 mg per nasogastric tube, produced significantly higher mean 24-h intragastric pH values relative to pantoprazole, 40 mg i.v., on both day 1 (3.05 vs 2.76, p < 0.002) and day 5 (3.65 vs 3.45, p = 0.024). Lansoprazole sustained the intragastric pH above 3 (days 1 and 5), 4, and 5 (day 1) significantly longer relative to pantoprazole. Lansoprazole's time to the maximum observed concentration and area under the plasma concentration-time curve over the 24-h time interval increased significantly from day I to day 5 (1.7 h vs 2.0 h and 1865 ng x h/ml vs 2091 ng x h/ml, respectively), and a significant increase in half-life relative to day 1 (0.96 h) was observed on day 5 (1.03 h) during pantoprazole treatment. CONCLUSION: Lansoprazole, 30 mg administered nasogastrically, effectively controls intragastric pH and is an alternative to i.v. pantoprazole in patients who are unable to swallow solid dosage formulations.

Quantification of fluoroscopic imaging system contrast by using video waveform monitoring.

A noninvasive method was developed for quantifying the overall contrast of fluoroscopic imaging systems within the clinical setting by using a simple phantom and common video test equipment. In this method, an acrylic phantom with four holes filled with varying amounts of air and aluminum is placed on the entrance exposure side of a patient-equivalent acrylic phantom. The air- and aluminum-filled holes provide a stepped gray-scale pattern that is displayed on the examination room viewing monitor when the phantom is fluoroscopically imaged under automatic brightness control. A video waveform monitor or oscilloscope is then used to quantify those video signal voltage levels as a contrast index value, which is defined as the maximum range of the video signal voltage levels of the gray-scale steps. The method is repeatable and allows quantification of the contrast of the imaging system. It can also be used to optimize video parameters, provide comparative data for quality control monitoring, and characterize overall contrast differences between systems. Experience with this method suggests that there is excellent correlation between the clinical perception of image contrast and the contrast index, with contrast index changes of approximately 15% being seen clinically.

Digital radiology equipment acquisition and installation procedures: a team approach at Mayo Clinic, Rochester, MN.

Digital imaging system integration is a complex process. A project team and a defined process for system planning, evaluation, and implementation can improve the chance for success. In this presentation, our project team relates their experiences.