Comparison of pharmaceutical properties and biological activities of prednisolone, deflazacort, and vamorolone in DMD disease models.

Duchenne muscular dystrophy (DMD) is a progressive disabling X-linked recessive disorder that causes gradual and irreversible loss of muscle, resulting in early death. The corticosteroids prednisone/prednisolone and deflazacort are used to treat DMD as the standard of care; however, only deflazacort is FDA approved for DMD. The novel atypical corticosteroid vamorolone is being investigated for treatment of DMD. We compared the pharmaceutical properties as well as the efficacy and safety of the three corticosteroids across multiple doses in the B10-mdx DMD mouse model. Pharmacokinetic studies in the mouse and evaluation of p-glycoprotein (P-gP) efflux in a cellular system demonstrated that vamorolone is not a strong P-gp substrate resulting in measurable central nervous system (CNS) exposure in the mouse. In contrast, deflazacort and prednisolone are strong P-gp substrates. All three corticosteroids showed efficacy, but also side effects at efficacious doses. After dosing mdx mice for two weeks, all three corticosteroids induced changes in gene expression in the liver and the muscle, but prednisolone and vamorolone induced more changes in the brain than did deflazacort. Both prednisolone and vamorolone induced depression-like behavior. All three corticosteroids reduced endogenous corticosterone levels, increased glucose levels, and reduced osteocalcin levels. Using micro-computed tomography, femur bone density was decreased, reaching significance with prednisolone. The results of these studies indicate that efficacious doses of vamorolone, are associated with similar side effects as seen with other corticosteroids. Further, because vamorolone is not a strong P-gp substrate, vamorolone distributes into the CNS increasing the potential CNS side-effects.

CycLing and EducATion (CLEAT): protocol for a single centre randomised controlled trial of a cycling and education intervention versus standard physiotherapy care for the treatment of hip osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disorder for which there is no known cure. Non-surgical management for people with mild-to-moderate hip OA focuses mainly on alleviating pain and maximising function via the National Institute for Health and Care Excellence (NICE) recommended combination of education and advice, exercise, and, where appropriate, weight loss. The CHAIN (Cycling against Hip pAIN) intervention is a group cycling and education intervention conceived as a way of implementing the NICE guidance. METHODS: CycLing and EducATion (CLEAT) is a pragmatic, two parallel arm, randomised controlled trial comparing CHAIN with standard physiotherapy care for the treatment of mild-to-moderate hip OA. We will recruit 256 participants referred to the local NHS physiotherapy department over a 24-month recruitment period. Participants diagnosed with hip OA according to NICE guidance and meeting the criteria for GP exercise referral will be eligible to participate. Primary outcome is the difference in Hip Disability and Osteoarthritis Outcome Score (HOOS) function, daily living subscale between those receiving CHAIN and standard physiotherapy care. Secondary outcomes include performance-based functional measures (40 m walking, 30s chair stand and stair climb tests), ability for patient to self-care (patient activation measure) and self-reported health-related resource use including primary and secondary care contacts. The primary economic endpoint is the number of quality adjusted life years (QALYs) at 24 weeks follow-up. The study is funded by the National Institute for Health Research, Research for Patient Benefit PB-PG-0816-20033. DISCUSSION: The literature identifies a lack of high-quality trials which inform on the content and design of education and exercise in the treatment of patients with hip OA and explore cost-effectiveness. CLEAT is a pragmatic trial which seeks to build further evidence of the clinical benefits of the CHAIN intervention compared to standard physiotherapy care within a randomised, controlled trial setting, and examine its cost-effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN19778222. Protocol v4.1, 24th October 2022.

Measuring the cost-effectiveness of treatments for people with multiple sclerosis: Beyond quality-adjusted life-years.

BACKGROUND: It is a familiar story. A promising multiple sclerosis (MS) treatment clears the three regulatory hurdles of safety, quality and efficacy, only to fall at the fourth: cost-effectiveness. This has led to concerns about the validity of the measures typically used to quantify treatment effects in cost-effectiveness analyses and in 2012, in the United Kingdom, the National Institute for Health and Care Excellence called for an improvement in the cost-effectiveness framework for assessing MS treatments. OBJECTIVE AND METHODS: This review describes what is meant by cost-effectiveness in health/social care funding decision-making, and usual practice for assessing treatment benefits. RESULTS: We detail the use of the quality-adjusted life-year (QALY) in resource allocation decisions, and set out limitations of this approach in the context of MS. CONCLUSION: We conclude by highlighting methodological and policy developments which should aid addressing these limitations.

Multidisciplinary residential home intervention to improve outcomes for frail residents.

BACKGROUND: Residential homes provide accommodation and assistance with personal care only and are not required to have registered nurses on site. However, their residents often have a combination of comorbidity, polypharmacy, frailty and mental-health conditions with poor access to healthcare to meet these needs. Integrated healthcare for older people is a key NHS priority in the Long-Term Plan and the Five-Year Forward View. We describe development and implementation of multi-disciplinary intervention to integrate healthcare and promote interprofessional education. METHODS: A multi-disciplinary residential home quality improvement project in two cycles by a team comprising senior and trainee general practitioners, trainees in geriatrics, psychiatry, pharmacist and residential home senior staff. The intervention was underpinned by the framework for enhanced health in care homes including Comprehensive Geriatric Assessment (CGA) and mental-health review. Each intervention session included an educational presentation by a team member consideration of each resident in a pre-evaluation multi-disciplinary discussion followed by a structured clinical assessment and discussion of proposed management. RESULTS: Three residential homes participated with a total 34 residents receiving intervention. In one residential home, there was a 75% reduction in admissions for those reviewed and a reduction in overall admission costs. Polypharmacy was reduced by an average of 2 medications per resident across the three sites. There was a 63% increase in cardio-pulmonary resuscitation decisions and 76% increase in advance care planning discussions. CONCLUSION: This was an effective model for multi-disciplinary trainees working with a perceived impact on physical and mental health, and valuable opportunities for sharing learning.

Exploring the Factors that Influence Workforce Participation for People with Multiple Sclerosis: A Discrete Choice Experiment.

Purpose Research indicates that employment is beneficial for people with multiple sclerosis (MS). However, people with MS typically face reduced workforce participation compared to the general population. Using a discrete choice experiment (DCE) we explored which factors are most important in influencing employment choices of people with MS, and whether the relative importance of factors differs between subgroups. Methods Attributes and levels for the DCE were developed using a systematic literature review and public involvement techniques with people with MS. In an online survey, respondents were asked to choose between two hypothetical job scenarios described using six attributes. We used a large, national register (the UK MS Register), to recruit participants aged 18-64 years with a diagnosis of MS. Choice data were analysed using multinomial logit and latent class models. Results Analyses were based on responses from 2350 people with MS. The preferred model specification was a latent class model, with three classes of respondent. The relative importance of attributes varied between classes, with one giving the greatest weight to the impact of work on other aspects of their lives, the second to having supportive bosses and colleagues, and the third to job flexibility. The classes differed significantly in terms of age and gender, type of MS, and socio-economic status. Conclusions Significant heterogeneity was apparent among people with MS regarding the factors that influence their employment decisions. Attributes concerning the impact of work, attitudes in the workplace and job flexibility appear more influential than those concerning physical workplace adaptations.

Metabolism and Disposition of Ataluren after Oral Administration to Mice, Rats, Dogs, and Humans.

Ataluren is a unique small molecule developed for the treatment of diseases caused by nonsense mutations, which result in premature termination of ribosomal translation and lack of full-length protein production. This study investigated the in vivo metabolism and disposition of ataluren in mice, rats, dogs, and humans. After single oral administration of [14C]ataluren, the overall recovery of radioactivity was ≥93.7%, with approximately 39%, 17%-21%, 12%, and 55% in the urine and 54%, 70%-72%, 80%, and 47% in the feces from intact mice, rats, dogs, and humans, respectively. In bile duct-cannulated (BDC) rats, approximately 10%, 7%, and 82% of the dose was recovered in the urine, feces, and bile, respectively, suggesting that biliary secretion was a major route for the elimination of ataluren in the rats. Ataluren was extensively metabolized after oral administration, and the metabolic profiles of ataluren were quantitatively similar across all species. Unchanged ataluren was the dominant radioactive component in plasma. Ataluren acyl glucuronide was the most prominent metabolite in plasma of all species and the dominant metabolite in BDC rat bile and human urine, whereas the oxadiazole cleavage products were the major or prominent metabolites in the feces of all species. Overall, the results indicate that phase I metabolism is negligible and that the pathway largely involves glucuronidation. No other circulatory conjugation metabolite was detected across investigated species. SIGNIFICANCE STATEMENT: Ataluren is a novel carboxylic acid-containing small molecule drug for treating nonsense mutation Duchenne muscular dystrophy. In vivo metabolism and disposition after a single dose of the drug were investigated in mice, rats, dogs, and humans. Phase I metabolism of ataluren was negligible, and the pathway largely involves glucuronidation. No other circulatory conjugation metabolite was detected across investigated species.

What Difference Does It Make? A Comparison of Health State Preferences Elicited From the General Population and From People With Multiple Sclerosis.

BACKGROUND: A major debate in the quality-adjusted life-year (QALY) literature concerns whose preferences should be used to estimate health state values (HSVs) and to calculate QALYs. OBJECTIVES: This study explores differences between public and patient values for multiple sclerosis (MS) health states, described using an MS-specific classification system (Multiple Sclerosis Impact Scale-8 Dimensions [MSIS-8D]). METHODS: The MSIS-8D is an existing preference-based measure of health-related quality of life in MS, which has 2 tariffs of HSVs, based on the preferences of a representative sample of the UK general population (n = 1702) and of people with MS living in the United Kingdom (n = 1635), elicited using the time trade-off technique. Here, we explore differences between HSVs by sample type, using descriptive statistics and multivariate regression methods. RESULTS: Overall, the survey of people with MS produced significantly higher HSVs; estimated values ranged from 0.079 to 0.883 for the general population survey and from 0.138 to 0.894 for the MS survey. Differences in HSVs were more pronounced for severe health states. The difference between patient and public values varied across the dimensions of the MSIS-8D. People with MS placed greater importance on cognition than the general population, leading to lower HSVs when impairment was at a worse level; the reverse was true for the daily activities, fatigue, and depression dimensions. CONCLUSIONS: We identified significant differences in HSVs by sample type. Using patient rather than public values may influence the results of economic evaluations, depending on the dimensions of health-related quality of life affected by the intervention being assessed, and may therefore have important consequences for reimbursement decisions.

Health State Values Derived from People with Multiple Sclerosis for a Condition-Specific Preference-Based Measure: Multiple Sclerosis Impact Scale-Eight Dimensions-Patient Version (MSIS-8D-P).

OBJECTIVE: In economic evaluation, health outcomes are commonly quantified using quality-adjusted life-years (QALYs) derived from the preferences of a sample of the general population. It can be argued that this approach ignores the preferences of people with experience of the condition, and that patient preferences have a place in the valuation of health outcomes. Here we report the estimation of a preference-based index for an existing condition-specific preference-based measure for multiple sclerosis (MS), the MSIS-8D, based on the preferences of people with MS. STUDY DESIGN: Internet time trade-off (TTO) survey, eliciting preferences from people with MS. METHODS: We elicited preferences from a sample of people with MS (N = 1635) across 169 MSIS-8D health states, using the TTO technique. We fitted ordinary least squares and random effects models to the survey data to estimate values for all health states described by the MSIS-8D. RESULTS: The new patient-derived index (the MSIS-8D-P) provides values ranging from 0.893 for the best possible health state to 0.138 for the worst state. The MSIS-8D-P exhibits good discriminative validity, identifying expected significant differences between groups based on presence/absence of MS, type of MS, and duration since diagnosis. CONCLUSIONS: The MSIS-8D-P index of values for MS-specific health states provides an opportunity to estimate QALYs based on patient preferences, for use in economic evaluations of treatments for MS. More broadly, it adds to the methods and data available to consider the health-related quality of life of people with MS to inform resource allocation and individual-level decisions regarding treatments for MS.

The experience of treatment barriers and their influence on quality of life in American Indian/Alaska Native breast cancer survivors.

BACKGROUND: American Indian and Alaska Native (AI/AN) breast cancer survivors experience disparities in breast cancer incidence and age-adjusted mortality compared with non-Hispanic white (NHW) breast cancer survivors. In addition, mortality-to-incidence rates indicate that AI/ANs continue to have the poorest survival from breast cancer compared with other racial groups. "Native American Cancer Education for Survivors" (NACES) is a cultural education and support intervention for AI/AN patients with cancer that collects data from voluntary participants through the NACES quality-of-life (QOL) survey regarding their cancer experience and survivor journey. METHODS: Data from the NACES QOL survey were analyzed to determine whether barriers accessing and during initial cancer treatment impacted QOL domains for AI/AN cancer survivors. Exploratory analyses of selected variables were conducted and were followed by Kruskal-Wallis tests to determine whether these barriers influenced survivorship QOL for AI/AN breast cancer survivors. RESULTS: AI/AN breast cancer survivors' social QOL was significantly affected by barriers to accessing cancer treatment. Many respondents experienced barriers, including a lack of cancer care at local clinics and the distance traveled to receive cancer care. During treatment, too much paperwork and having to wait too long in the clinic for cancer care were the most frequently reported barriers. CONCLUSIONS: Treatment barriers influence AI/AN breast cancer survivors' social QOL. Mediating these barriers is crucial to ameliorating AI/AN survivors' disparities when accessing and completing cancer treatment and improving survivorship QOL. Cancer 2017;123:861-68. © 2016 American Cancer Society.

A Quality-Adjusted Life-Year Measure for Multiple Sclerosis: Developing a Patient-Reported Health State Classification System for a Multiple Sclerosis-Specific Preference-Based Measure.

BACKGROUND: Increasingly, generic preference-based measures of health-related quality of life (HRQOL) are used to estimate quality-adjusted life-years to inform resource allocation decisions. Evidence suggests that generic measures may not be appropriate for multiple sclerosis (MS). OBJECTIVES: To report the first stage in the development of an MS-specific preference-based measure to quantify the impact of MS and its treatment: deriving a health state classification system, which is amenable to valuation, from the 29-item Multiple Sclerosis Impact Scale (MSIS-29), a widely used patient-reported outcome measure in MS. METHODS: The dimensional structure of the MSIS-29 was determined using factor analysis and a conceptual framework of HRQOL in MS. Item performance was assessed, using Rasch analysis and psychometric criteria, to enable the selection of one item to represent each dimension of HRQOL covered by the MSIS-29. Analysis was undertaken using a sample (N = 529) from a longitudinal study of people with MS. Results were validated by repeating the analysis with a second sample (N = 528). RESULTS: Factor analysis confirmed the two-subscale structure of the MSIS-29. Both subscales covered several conceptually independent dimensions of HRQOL. Following Rasch and psychometric analysis, an eight-dimensional classification system named the MSIS-8D was developed. Each dimension was represented by one item with four response levels. CONCLUSIONS: Combining factor analysis with conceptual mapping, and Rasch analysis with psychometric criteria, provides a valid method of constructing a classification system for an MS-specific preference-based measure. The next stage is to obtain preference weights so that the measure can be used in studies investigating MS.

Estimating a Preference-Based Index for an Eight-Dimensional Health State Classification System for Multiple Sclerosis.

BACKGROUND: Condition-specific measures are frequently used to assess the health-related quality of life of people with multiple sclerosis (MS). Such measures are unsuitable for use in economic evaluations that require estimates of cost per quality-adjusted life-year because they are not based on preferences. OBJECTIVES: To report the estimation of a preference-based single index for an eight-dimensional instrument for MS, the Multiple Sclerosis Impact Scale - Eight Dimensions (MSIS-8D), derived from an MS-specific measure of health-related quality of life, the 29-item Multiple Sclerosis Impact Scale (MSIS-29). METHODS: We elicited preferences for a sample of MSIS-8D states (n = 169) from a sample (n = 1702) of the UK general population. Preferences were elicited using the time trade-off technique via an Internet-based survey. We fitted regression models to these data to estimate values for all health states described by the MSIS-8D. Estimated values were assessed against MSIS-29 scores and values derived from generic preference-based measures in a large, representative sample of people with MS. RESULTS: Participants reported that the time trade-off questions were easy to understand. Observed health state values ranged from 0.08 to 0.89. The best-performing model was a main effects, random effects model (mean absolute error = 0.04). Validation analyses support the performance of the MSIS-8D index: it correlated more strongly than did generic measures with MSIS-29 scores, and it discriminated effectively between subgroups of people with MS. CONCLUSIONS: The MSIS-8D enables health state values to be estimated from the MSIS-29, adding to the methods available to assess health outcomes and to estimate quality-adjusted life-years for MS for use in health technology assessment and decision-making contexts.

Mental Imagery to Reduce Alcohol-related harm in patients with alcohol use disorder and alcohol-related liver damaGE: the MIRAGE randomised pilot trial results.

OBJECTIVE: The healthcare burden of alcohol-related liver disease (ARLD) is increasing. ARLD and alcohol use disorder (AUD) is best managed by reduction or cessation of alcohol use, but effective treatments are lacking. We tested whether people with ARLD and AUD admitted to hospital could be recruited to and retained in a trial of Functional Imagery Training (FIT), a psychological therapy that uses mental imagery to reduce alcohol craving. We conducted a multicentre randomised pilot trial of treatment as usual (TAU) versus FIT+TAU in people admitted to hospital with ARLD and AUD. DESIGN: Participants were randomised to TAU (a single session of brief intervention) or FIT+TAU (TAU with one hospital-based FIT session then eight telephone sessions over 6 months). Pilot outcomes included recruitment rate and retention at day 180. Secondary outcomes included fidelity of FIT delivery, alcohol use, and severity of alcohol dependence. RESULTS: Fifty-four participants (mean age 49; 63% male) were recruited and randomised, 28 to TAU and 26 to FIT+TAU. The retention rate at day 180 was 43%. FIT was delivered adequately by most alcohol nurses. 50% of intervention participants completed FIT sessions 1 and 2. There were no differences in alcohol use or severity of alcohol dependence between treatment groups at day 180. CONCLUSION: Participants with ARLD and AUD could be recruited to a trial of FIT versus FIT+TAU. However, retention at day 180 was suboptimal. Before conducting a definitive trial of FIT in this patient group, modifications in the intervention and recruitment/retention strategy must be tested. TRIAL REGISTRATION NUMBER: ISRCTN41353774.

Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients.

Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. ClinicalTrials.gov registration: NCT01557400.

Mental Imagery to Reduce Alcohol-related harm in patients with alcohol dependence and alcohol-related liver damaGE: the MIRAGE pilot trial protocol.

INTRODUCTION: In the UK, alcohol use is the main driver of chronic liver disease and each year results in over 1 million unplanned hospital admissions and over 25 000 deaths from alcohol-related liver disease (ArLD). The only effective treatment to prevent progression of liver damage is reducing or ceasing alcohol consumption. Psychological and pharmacological therapies for alcohol misuse are ineffective in patients with ArLD. Functional imagery training (FIT) is a novel psychological therapy that builds on motivational interviewing techniques with multisensory imagery. This pilot trial aims to test the feasibility of training alcohol liaison nurses to deliver FIT therapy and of recruiting and retaining patients with ArLD and alcohol dependence to a randomised trial of FIT and treatment as usual (TAU) versus TAU alone. METHODS AND ANALYSIS: This is a randomised pilot trial of FIT and TAU versus TAU alone in 90 patients with ArLD and alcohol dependence admitted to one of four UK centres. The primary objectives are to estimate rates of screening, recruitment, randomisation, retention, adherence to FIT/TAU and a preliminary assessment of the FIT intervention in the ArLD population. Data from the pilot study will be used to finalise the design of a definitive randomised controlled trial to assess the effectiveness and cost-effectiveness of FIT. The proposed primary outcome measure for the definitive trial is self-reported alcohol use assessed using timeline follow-back. ETHICS AND DISSEMINATION: Research ethics approval was given by the Yorkshire and Humber-Bradford Leeds Research Ethics Committee (reference: 21/YH/0044). Eligible patients will be approached and written informed consent obtained prior to participation. Results will be disseminated through peer-reviewed open access journals, international conferences and a lay summary published on the Trials Unit website and made available to patient groups. TRIAL REGISTRATION NUMBER: ISRCTN41353774.

Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia.

Blocking the pyrimidine nucleotide de novo synthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH) results in the cell cycle arrest and/or differentiation of rapidly proliferating cells including activated lymphocytes, cancer cells, or virally infected cells. Emvododstat (PTC299) is an orally bioavailable small molecule that inhibits DHODH. We evaluated the potential for emvododstat to inhibit the progression of acute myeloid leukemia (AML) using several in vitro and in vivo models of the disease. Broad potent activity was demonstrated against multiple AML cell lines, AML blasts cultured ex vivo from patient blood samples, and AML tumor models including patient-derived xenograft models. Emvododstat induced differentiation, cytotoxicity, or both in primary AML patient blasts cultured ex vivo with 8 of 10 samples showing sensitivity. AML cells with diverse driver mutations were sensitive, suggesting the potential of emvododstat for broad therapeutic application. AML cell lines that are not sensitive to emvododstat are likely to be more reliant on the salvage pathway than on de novo synthesis of pyrimidine nucleotides. Pharmacokinetic experiments in rhesus monkeys demonstrated that emvododstat levels rose rapidly after oral administration, peaking about 2 hours post-dosing. This was associated with an increase in the levels of dihydroorotate (DHO), the substrate for DHODH, within 2 hours of dosing indicating that DHODH inhibition is rapid. DHO levels declined as drug levels declined, consistent with the reversibility of DHODH inhibition by emvododstat. These preclinical findings provide a rationale for clinical evaluation of emvododstat in an ongoing Phase 1 study of patients with relapsed/refractory acute leukemias.

A group-based behavioural intervention for weight management (PROGROUP) versus usual care in adults with severe obesity: a feasibility randomised controlled trial protocol.

BACKGROUND: Approximately 15 million people in the UK live with obesity, around 5 million of whom have severe obesity (body mass index (BMI) ≥35kg/m2). Having severe obesity markedly compromises health, well-being and quality of life, and substantially reduces life expectancy. These adverse outcomes are prevented or ameliorated by weight loss, for which sustained behavioural change is the cornerstone of treatment. Although NHS specialist 'Tier 3' Weight Management Services (T3WMS) support people with severe obesity, using individual and group-based treatment, the current evidence on optimal intervention design and outcomes is limited. Due to heterogeneity of severe obesity, there is a need to tailor treatment to address individual needs. Despite this heterogeneity, there are good reasons to suspect that a structured group-based behavioural intervention may be more effective and cost-effective for the treatment of severe obesity compared to usual care. The aims of this study are to test the feasibility of establishing and delivering a multi-centre randomised controlled clinical trial to compare a group-based behavioural intervention versus usual care in people with severe obesity. METHODS: This feasibility randomised controlled study is a partially clustered multi-centre trial of PROGROUP (a novel group-based behavioural intervention) versus usual care. Adults ≥18 years of age who have been newly referred to and accepted by NHS T3WMS will be eligible if they have a BMI ≥40, or ≥35 kg/m2 with comorbidity, are suitable for group-based care and are willing to be randomised. Exclusion criteria are participation in another weight management study, planned bariatric surgery during the trial, and unwillingness or inability to attend group sessions. Outcome assessors will be blinded to treatment allocation and success of blinding will be evaluated. Clinical measures will be collected at baseline, 6 and 12 months post-randomisation. Secondary outcome measures will be self-reported and collected remotely. Process and economic evaluations will be conducted. DISCUSSION: This randomised feasibility study has been designed to test all the required research procedures and additionally explore three key issues; the feasibility of implementing a complex trial at participating NHS T3WMS, training the multidisciplinary healthcare teams in a standard intervention, and the acceptability of a group intervention for these particularly complex patients. TRIAL REGISTRATION: ISRCTN number 22088800.

What drives differences in preferences for health states between patients and the public? A qualitative investigation of respondents' thought processes.

Cost-effectiveness analyses using quality-adjusted life-years (QALYs) are used in decision-making regarding which interventions are available via many national healthcare systems. QALYs are calculated based on health state values provided by preference elicitation techniques. Several national decision-making bodies recommend that health state values should be based on preferences elicited from general populations, rather than from patients. Previous studies have shown systematic differences between health state values elicited from members of the general population and from patients. Various explanations for this phenomenon have been proposed, however empirical evidence for these is scarce. We aimed to explore possible reasons for discrepancies between public and patient valuations by undertaking qualitative cognitive interviews, asking 14 members of the general population and 12 people with multiple sclerosis (MS) to think aloud while completing a preference elicitation task (time trade-off) for MS-related health states. The interviews were undertaken between December 2016 and October 2017 in the South West region of England, and were analysed using the Framework Method. As anticipated, we found that participants with MS had more experience of health problems and used this experience to consider how they might adapt to the health states over time, and which dimensions of health-related quality of life were most important to them. We found no evidence that participants with MS were less affected by framing effects and focusing illusions, more likely to prioritise non-physical dimensions of health, or more prone to loss aversion, endowment effects and non-compensatory decision-making. These findings contribute to our understanding of how patients and members of the general population respond to preference elicitation exercises, and why their preferences may differ, and may help to inform developing areas of research, such as the joint presentation of cost-effectiveness results from multiple perspectives, and the use of preferences elicited from patients for experienced health states.

Involving Patients in Health Economics Research: "The PACTS Principles".

Discussion of public and patient involvement (PPI) in health economics (HE) research is growing. There is much literature on PPI principles and standards, but little specifically regarding involving patients in HE research. Here, we outline "PACTS", a set of principles, developed with a PPI group, for considering patient involvement in HE research. Planning: Involvement is best built in to research plans from the outset. This includes setting specific goals for involvement activities, and clearly communicating the background and purpose of involvement. Approach selection: We describe two main approaches to involvement-discussion-based and task-based. Discussion-based approaches are useful for generating broad insights and revealing "unknown unknowns". Task-based approaches offer a more focused means of shedding light on "known unknowns". Continuous involvement: Involving patients throughout the research process and across a range of projects helps build expertise for patients and insight for HE researchers. Team building: Meaningful involvement creates a shared sense of ownership of the research and, over time, helps to develop a team ethos, enhancing the positive impacts of involvement. Sensitivity: HE research can be perceived as technical and impersonal. Addressing this requires sensitivity, clarity, and an honest and open approach. There is increased recognition that patient contributors are experts at providing a "lived experience" perspective, in the way that clinicians are experts at providing an overview of conditions and HEs are experts in the methodology of their discipline. We hope these "PACTS Principles" complement existing PPI approaches and provide a useful foundation for health economists considering patient involvement.

Pharmacokinetics and Safety of PTC596, a Novel Tubulin-Binding Agent, in Subjects With Advanced Solid Tumors.

PTC596 is a novel, orally bioavailable, small-molecule tubulin-binding agent that reduces B-cell-specific Moloney murine leukemia virus insertion site 1 activity and is being developed for the treatment of solid tumors. A phase 1, open-label, multiple-ascending-dose study was conducted to evaluate the pharmacokinetics and safety of the drug in subjects with advanced solid tumors. PTC596 was administered orally biweekly based on body weight. Dose escalation followed a modified 3 + 3 scheme using doses of 0.65, 1.3, 2.6, 5.2, 7.0, and 10.4 mg/kg. Following oral administration, PTC596 was rapidly absorbed, and between 0.65 and 7.0 mg/kg reached a maximum plasma concentration 2 to 4 hours after dosing. Area under the plasma concentration-time curve increased proportionally with body weight-adjusted doses. Maximum plasma concentration increased with dose, although the increase was less than dose proportional at dose levels >2.6 mg/kg. No accumulation occurred after multiple administrations up to 7.0 mg/kg. PTC596 had a terminal half-life ranging 12 to 15 hours at all doses except for the highest dose of 10.4 mg/kg, where the half-life was approximately 20 hours. Overall, PTC596 was well tolerated. The most frequently reported PTC596-related treatment-emergent adverse events were mild to moderate gastrointestinal symptoms, including diarrhea (54.8%), nausea (45.2%), vomiting (35.5%), and fatigue (35.5%). Only 1 patient treated with 10.4 mg/kg experienced dose-limiting toxicity of neutropenia and thrombocytopenia, both of which were reversible. Stable disease as best overall response was observed among 7 patients, with 2 patients receiving the study drug up to 16 weeks. These results support the further development of PTC596 for the treatment of solid tumors.

The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines.

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.