Incorporating development of a patient-reported outcome instrument in a clinical drug development program: examples from a heart failure program.

BackgroundPatient-reported outcome (PRO) measures can be used to support label claims if they adhere to US Food & Drug Administration guidance. The process of developing a new PRO measure is expensive and time-consuming. We report the results of qualitative studies to develop new PRO measures for use in clinical trials of omecamtiv mecarbil (a selective, small molecule activator of cardiac myosin) for patients with heart failure (HF), as well as the lessons learned from the development process.MethodsConcept elicitation focus groups and individual interviews were conducted with patients with HF to identify concepts for the instrument. Cognitive interviews with HF patients were used to confirm that no essential concepts were missing and to assess patient comprehension of the instrument and items.ResultsDuring concept elicitation, the most frequently reported HF symptoms were shortness of breath, tiredness, fluid retention, fatigue, dizziness/light-headedness, swelling, weight fluctuation, and trouble sleeping. Two measures were developed based on the concepts: the Heart Failure Symptom Diary (HF-SD) and the Heart Failure Impact Scale (HFIS). Findings from cognitive interviews suggested that the items in the HF-SD and HFIS were relevant and well understood by patients. Multiple iterations of concept elicitation and cognitive interviews were needed based on FDA request for a broader patient population in the qualitative study. Lessons learned from the omecamtiv mecarbil PRO/clinical development program are discussed, including challenges of qualitative studies, patient recruitment, expected and actual timelines, cost, and engagement with various stakeholders.ConclusionDevelopment of a new PRO measure to support a label claim requires significant investment and early planning, as demonstrated by the omecamtiv mecarbil program

Ultimate pH values and bacteriological condition of meat and stress metabolites in blood of transported reindeer bulls

Twenty-three reindeer bulls, aged 2-3 years, fed during two winter months at the Vuolda reindeer research station in Arjeplog, Sweden, were used in the study. The first group of eight reindeer was moved from their feeding corral to a selection corral, captured by lasso and stunned with a captive bolt outside the selection corral. The second group of seven reindeer was moved to the selection corral, captured by lasso and restrained, after which they were loaded onto a lorry- and transported for 1 hour and then slaughtered. The third group of eight reindeer was moved to the selection corral and herded directly onto the lorry, without any manual handling. They were transported for 5 h and then slaughtered. In both transport groups, four reindeer were fitted with pre-programmed automatic blood sampling equipment (ABSE). ABSE sampled blood at predetermined times via a jugular vein catheter. Ultimate pH-values in three muscles (Mm. longissimus, triceps brachii and biceps femoris) were significantly lower in the group carefully handled and transported for 5 h compared with the other two groups. The physiological mechanisms behind these results are discussed. Samples from M. semimembranosus were collected at slaughter and after 2, 6 and 10 days of refrigerated storage (+4 °C). The samples were analysed for total counts of aerobic bacteria (pour-plated in Tryptone Glucose Extract Agar, Difco, incubated at 20 °C and 30 °C, respectively for 72 h), coliform bacteria 37 °C (pour-plated in Violet Red Bile Agar, Oxoid, incubated at 37 °C for 24 h), Enterococci (surface-plated onto Slantez and Bartley Agar, Oxoid, incubated at 44 °C for 48 h) and Bacillus cereus (surface-plated onto Blood Agar Plates (Blood Agar Base, Difco, supplemented with 5% defibrinated horse blood) 30 °C for 24 h). All samples fell in the range 'fit for consumption'. At slaughter, there was no difference in ASAT activity, urea and Cortisol concentrations between the two transported groups. However, the plasma ASAT activity and urea concentrations at slaughter were significantly lower in the non-transported group. In both transport groups, the plasma Cortisol concentrations increased during loading onto and unloading from the lorry. Abomasal lesions were observed in all treatment groups. It was concluded that reindeer showed an acute stress response to manual handling and transport

Key aspects of statin intolerance leading to treatment discontinuation: a patient perspective

Abstract Background and aims Statins are the standard of care for patients with dyslipidemia, but some patients develop intolerance to treatment. The experience of statin intolerant (SI) patients is poorly understood. The objective of this study was to identify key aspects of SI that may be associated with treatment discontinuation. Methods Using a previously created questionnaire, we conducted a pilot cross-sectional survey to identify items important for describing patient-centric aspects of SI. The study recruited adult (18+) patients with a history of statin-associated side effects from 9 clinics in 6 countries (France, Italy, Norway, Spain, Sweden, and the United Kingdom), who had received statin treatment within the previous two years. Results We surveyed 104 patients (mean age 61.5 SD=11.2 years, 63.5% men, 50% currently on statins). Patients most frequently reported muscle-related symptoms: pain (90.9%), cramps (63.7%), and stiffness (58.2%). Using a 0–10 point scale, significant differences were found between those continuing versus discontinuing their statins for being bothered by side effects (7.5 vs 9.2, p=0.001), for an inability to tolerate side effects (6.7 vs 9.0, p<0.001), and those having too much side effects interference with their daily life (5.7 vs 8.6, p<0.001; see figure). For patients whose doctors worked on adjusting statin regimen, 67% stayed on treatment; for those whose doctors did not, only 10% continued treatment. Conclusions Results of this pilot survey suggest patients who experience greater side effects severity and interference with daily activity, along with lower efforts by clinicians to work with adjusting their statin regimen, are at greater risk for discontinuing treatment. A wider survey and larger study population is needed to confirm the results of this pilot study. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Amgen Inc

Posterior reconstruction during robotic-assisted radical cystectomy with intracorporeal orthotopic ileal neobladder: description and outcomes of a simple step

A posterior reconstruction (PR) might improve the fluidity and delicacy of the maneuvers related to the neovesico-urethral anastomosis during robotic-assisted radical cystectomy (RARC). Our objective is to describe in detail the surgical steps of PR and to assess its feasibility and functional outcomes. The data regarding patients undergoing a totally intracorporeal RARC with neobladder and PR for high-grade and/or muscle-invasive urothelial cancer of the bladder at Karolinska University Hospital between October 2015 and November 2016 by a single surgeon (PW) were reviewed. Prior to the anastomosis, a modified posterior Rocco’s repair involving the Denonvillier’s fascia, the rhabdosphincter, and the posterior side of the ileal neobladder neck was performed. The steps are shown in a video at https://doi.org/10.1089/vid.2019.0029. The primary outcome was urinary continence; the secondary outcomes were urinary leakage, intermittent catheterization, and complications related to the reconstructive steps. Eleven male patients with a median age and BMI of 67 years and 24, respectively, underwent RARC with PR associated to the neovesico-urethral anastomosis. Overall and posterior reconstruction time were 300′ (195–320) and 6′ (4–7), respectively. The daytime and nighttime continence rates were 100% and 44% at 12 months, respectively; the median pad weight was 3.5 g and 108 g at daytime and nighttime, respectively. One urinary leakage from the urethrovesical anastomosis was treated conservatively. Two patients perform intermittent catheterization. The posterior reconstruction during RARC is safe and feasible, providing good continence rates. It supported a careful suturing of the anastomosis as well as an uncomplicated catheter placement

Web accessibility by Morse Code modulated haptics for deaf-blind

ABSTRACT Providing information using a modality that is both non-visual and non-auditory such as haptic feedback, may be a viable approach regarding web accessibility for deaf-blind. Haptic navigation systems have been shown to be easy to lear

The development of a new measure of quality of life in the management of gastro-oesophageal reflux disease: the Reflux Questionnaire.

INTRODUCTION This paper reports on the development of a new measure of health-related quality of life for use among patients with gastro-oesophageal reflux disease (GORD), funded as part of the REFLUX trial. This is a large UK multi centre trial that aims to compare the clinical and cost effectiveness of minimal access surgery with best medical treatment for patients with GORD within the NHS. Method Potential items were identified via a series of interviews and focus groups carried out with patients who were receiving/had received medical or surgical treatment for GORD. The final measure consisted of 31 items covering 7 categories (Heartburn; Acid reflux; Wind; Eating and swallowing; Bowel movements; Sleep; Work, physical and social activities). The measure produced two outputs: a quality of life score (RQLS) and five Reflux symptom scores. Reliability (internal consistency), criterion validity with the SF-36 and, sensitivity to change in terms of relationship with reported change in prescribed medication were assessed amongst a sample of 794 patients recruited into the trial. RESULTS The measure was shown to be internally consistent, to show criterion validity with the SF-36 and sensitive to changes in patients use of prescribed medication at baseline and 3 month follow-up. DISCUSSION The Reflux questionnaire is a new self-administered questionnaire for use amongst patients with GORD. Initial findings suggest that the new measure is valid, reliable, acceptable to respondents and simple to administer in both a clinical and research context