Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254.

BACKGROUND: GSK3640254 (GSK'254) is a next-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy. METHODS: This phase IIa double-blind (sponsor-unblinded), randomized, placebo-controlled, adaptive study evaluated antiviral effect, safety, tolerability, and PK of once-daily GSK'254 monotherapy administered with food (moderate-fat meal) in HIV-1-positive, treatment-naive adults. In part 1, participants received GSK'254 10 or 200 mg for 10 days. In part 2, participants received GSK'254 40, 80, or 140 mg for 7 days, modified from 10 days by a protocol amendment to decrease potential for resistance-associated mutations (RAMs). The primary endpoint was maximum change from baseline in HIV-1 RNA. RESULTS: Maximum changes in HIV-1 RNA of -0.4, -1.2, -1.0, -1.5, and -2.0 log10 occurred with GSK'254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses ≥40 mg resulted in ≥1-log10 declines in HIV-1 RNA. Plasma PK was generally dose proportional to 140 mg but non-proportional between 140 and 200 mg. Four participants in the 200-mg group developed RAMs on day 11 in part 1, 1 with phenotypic resistance. No RAMs occurred in part 2. Adverse events (AEs) were reported by 22 (65%) participants; headache was the most common (n = 4). Two non-drug-related serious AEs occurred. All AEs were of mild-to-moderate intensity, except for 2 grade 3 non-drug-related AEs in 1 participant. CONCLUSIONS: This monotherapy study established a dose-antiviral response relationship for GSK'254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216). CLINICAL TRIALS REGISTRATION: NCT03784079.

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

AIMS: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women. METHODS: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC0-t ), maximum observed concentration (Cmax ) and plasma concentration at the end of the dosing interval (Cτ ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored. RESULTS: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0-t , Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. CONCLUSION: Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.

A Phase IIa Study Evaluating Safety, Pharmacokinetics, and Antiviral Activity of GSK2838232, a Novel, Second-generation Maturation Inhibitor, in Participants With Human Immunodeficiency Virus Type 1 Infection.

BACKGROUND: GSK2838232 is a second-generation, potent, small-molecule, oral human immunodeficiency virus type 1 (HIV-1) maturation inhibitor for once-daily administration boosted with a pharmacoenhancer. METHODS: The phase 2a, proof-of-concept study was an open-label, adaptive dose-ranging design. Safety, pharmacokinetics, and efficacy of GSK2838232 boosted by cobicistat were evaluated in individuals with HIV-1 infection. The study participants (N = 33) received GSK2838232 once daily across a range of doses (20-200 mg) with cobicistat 150 mg for 10 days. RESULTS: GSK2838232 was safe and well tolerated with no clinically meaningful changes in safety parameters or adverse events. Exposure (maximum concentration and area under the concentration-time curve from time zero to the concentration at 24 hours postdose) increased 2- to 3-fold with repeated dosing in an approximately dose-proportional manner, reaching steady-state by day 8 with a half-life (t½) from 16.3 to 19.2 hours. Clearance and t½ values were not dependent on dose. Viral load declined from baseline with all GSK2838232 doses. Mean maximum declines from baseline to day 11 in HIV-1 RNA log10 copies/mL with the 20-mg, 50-mg, 100-mg, and 200-mg cohorts were -0.67, -1.56, -1.32, and -1.70, respectively. CD4+ cell counts increased at doses ≥50 mg. CONCLUSIONS: GSK2838232 with cobicistat was well tolerated and exhibited efficacy as a short-term monotherapy in participants with HIV-1. This positive proof-of-concept study supports the continued development of GSK2838232 for the treatment of HIV as part of combination antiretroviral therapy. CLINICAL TRIALS REGISTRATION: NCT03045861.

Does Quantitative Research in Child Maltreatment Tell the Whole Story? The Need for Mixed-Methods Approaches to Explore the Effects of Maltreatment in Infancy.

Background and Aims. Research on child maltreatment has largely overlooked the under-five age group and focuses primarily on quantitative measurement. This mixed-methods study of maltreated children (N = 92) entering care (age 6-60 months) combines a quantitative focus on the associations between care journey characteristics and mental health outcomes with a qualitative exploration of maltreatment in four different families. Methods. Care journey data was obtained from social care records; mental health and attachment assessments were carried out following entry to care; qualitative data comprised semistructured interviews with professionals, foster carers, and parents. Results. Significant associations were found between suspected sexual abuse and increased DAI inhibited attachment symptoms (p = 0.001) and between reported domestic violence and decreased DAI inhibited (p = 0.016) and disinhibited (p = 0.004) attachment symptoms. Qualitative results: two themes demonstrate the complexity of assessing maltreatment: (1) overlapping maltreatment factors occur in most cases and (2) maltreatment effects may be particularly challenging to isolate. Conclusions. Qualitative exploration has underscored the complexity of assessing maltreatment, indicating why expected associations were not found in this study and posing questions for the quantitative measurement of maltreatment in general. We therefore suggest a new categorisation of maltreatment and call for the complimentary research lenses of further mixed-methods approaches.

The feasibility of a randomised controlled trial of Dyadic Developmental Psychotherapy.

BACKGROUND: Maltreated children have significant and complex problems which clinicians find difficult to diagnose and treat. Previous US pilot work suggests that Dyadic Developmental Psychotherapy (DDP) may be effective; however, rigorous evidence from a randomised controlled trial (RCT) is lacking. The purpose of this study is to establish the feasibility of an RCT of DDP by exploring the ways that DDP is operating across different UK sites and the impacts of current practice on the potential set-up of an RCT. METHODS: Qualitative methods (interviews, focus groups and teleconferences) were used to explore trial feasibility with therapists and service managers from teams implementing both DDP and possible control interventions. Data were analysed thematically and related to various aspects of trial design. RESULTS: DDP was commonly regarded as having a particular congruence with the complexity of maltreatment-associated problems and a common operating model of DDP was evident across sites. A single control therapy was harder to establish, however, and it is likely to be a non-specific and context-dependent intervention/s offered within mainstream Child and Adolescent Mental Health Services (CAMHS). Because a 'gold standard' Treatment as Usual (TAU) does not currently exist, randomisation between DDP and TAU (CAMHS) therefore looks feasible and ethical. The nature of family change during DDP was regarded as multi-faceted, non-linear and relationship-based. Assessment tools need to be carefully considered in terms of their ability to capture change that covers both individual child and family-based functioning. CONCLUSIONS: An RCT of DDP is feasible and timely. This study has demonstrated widespread interest, support and engagement regarding an RCT and permissions have been gained from sites that have shown readiness to participate. As maltreated children are among the most vulnerable in society, and as there are currently no treatments with RCT evidence, such a trial would be a major advance in the field.

Examining the feasibility of an economic analysis of dyadic developmental psychotherapy for children with maltreatment associated psychiatric problems in the United Kingdom.

BACKGROUND: Children with maltreatment associated psychiatric problems are at increased risk of developing behavioural or mental health disorders. Dyadic Developmental Psychotherapy (DDP) was proposed as treatment for children with maltreatment histories in the USA, however, being new to the UK little is known of its effectiveness or cost-effectiveness. As part of an exploratory study, this paper explores the feasibility of undertaking economic analysis of DDP in the UK. METHODS: Feasibility for economic analysis was determined by ensuring such analysis could meet key criteria for economic evaluation. Phone interviews were conducted with professionals (therapists trained and accredited or in the process of becoming accredited DDP practitioners). Three models were developed to represent alternative methods of DDP service delivery. Once appropriate comparators were determined, economic scenarios were constructed. Cost analyses were undertaken from a societal perspective. Finally, appropriate outcome measurement was explored through clinical opinion, literature and further discussions with clinical experts. RESULTS: Three DDP models were constructed: DDP Full-Basic, DDP Home-Based and DDP Long-Term. Two potential comparator interventions were identified and defined as Consultation with Carers and Individual Psychotherapy. Costs of intervention completion per case were estimated to be: £6,700 (DDP Full-Basic), £7,100 (Consultations with Carers), £7,200 (DDP Home-Based), £11,400 (Individual Psychotherapy) and £14,500 (DDP Long-Term). None of the models of service delivery were found to currently measure effectiveness consistently. The Strengths and Difficulties Questionnaire (SDQ) was deemed an appropriate primary outcome measure, however, it does not cover all disorders DDP intends to treat and the SDQ is not a direct measure of health gain. Inclusion of quality of life measurement is required for comprehensive economic analysis. CONCLUSIONS: Economic analysis of DDP in the UK is feasible if vital next steps are taken to measure intervention outcomes consistently, ideally with a quality of life measurement. An economic analysis using the models constructed could determine the potential cost-effectiveness of DDP in the UK and identify the most efficient mode of service delivery.

The expansion of nurse prescribing in Scotland: an evaluation.

Medicine prescribing by community nurses commenced in the UK in 1996. By 2001, nurse prescribing was extended to include more nurses and to cover a wider formulary. This research project provides an evaluation of the extension of prescribing powers to nurses in Scotland, following the introduction of legislation in 2001. It aimed to evaluate the impact of nurse prescribing powers on patients, nurses, prescribers, and other stakeholders. A range of methods were used, including two public surveys, stakeholder interviews, postal questionnaires and case studies. The benefits of extended nurse prescribing include: improved patient access to treatment; enhanced patient care; enabled more effective use of medical staff time and greater professional satisfaction for nurses who used nursing skills; and built inter-professional working. Some obstacles existed, including organisational, institutional and resource factors that restricted the overall success of the extension of nurse prescribing. There are high levels of agreement between patients, the public, nurse prescribers, physicians and other health professionals about the benefits of nurse prescribing to patients. The extension of nurse prescribing has been largely successful, with some organisational and procedural areas that could be addressed.

Escaping the inescapable: Risk of mental health disorder, somatic symptoms and resilience in Palestinian refugee children.

Exposure to war, conflict and forced migration puts children at risk of mental health problems. The present study examined the levels of psychological distress and resilience factors among 106 Palestinian refugee children aged 11 to 17 in the West Bank. In a cross-sectional, mixed method design along with qualitative interviews, three questionnaires were administered: the Strength and Difficulties Questionnaire and Patient Health Questionnaire-15, assessed the risk of mental health disorders and psychosomatic complaints, and the Child and Youth Resilience Measure assessed the availability of resilience-enhancing factors. Palestinian refugee children were found to be at greater risk for mental disorders and psychosomatic complaints than were children living in non-conflict affected settings. In addition, resilience-enhancing resources were significantly reduced and were negatively correlated with both symptom outcomes. Risk factors identified included poverty, violence and marginalisation. Key protective factors were youth education, supportive relationships and social participation. Our findings support interventions that address the identified protective factors, which may promote the mental health of this vulnerable population.

Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor.

Despite advances in HIV-1 management with antiretroviral therapy, drug resistance and toxicities with multidrug regimens can result in treatment failure. Hence, there is a continuing demand for antiretroviral agents (ARVs) with novel mechanisms of action. Maturation inhibitors inhibit HIV-1 replication via a unique mechanism of action and can be combined with other ARVs. Two phase I randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, to determine safety, pharmacokinetics (NCT03231943), and relative bioavailability (NCT03575962) in healthy adults. The first trial was conducted in two parts. Part 1 was conducted in a two-cohort, interlocking, eight-period fashion in 20 participants with single ascending doses of GSK3640254 (1-700 mg) or placebo. In Part 2, 58 participants were randomized to receive GSK3640254 (n = 44) or placebo (n = 14). Four participants reported adverse events (AEs) leading to study discontinuation, with one adverse drug reaction (maculopapular rash). There was no relationship between frequency or severity of AEs and dose. Pharmacokinetic assessments showed that GSK3640254 was slowly absorbed, with time to maximum concentration (tmax) occurring between 3.5 and 4 hours and half-life of ~24 hours. In the relative bioavailability study of GSK3640254 mesylate salt vs bis-hydrochloride salt capsules in 14 healthy adults, the mesylate salt performed slightly better than the bis-hydrochloride formulation (12%-16% increase in area under the concentration-time curve and maximum concentration); tmax (5 hours) was similar between the formulations. Initial pharmacokinetic and safety data from these healthy-participant studies informed further development of GSK3640254 for once-daily dosing for the treatment of HIV-1 infection.

Clout or doubt? Perspectives on an infant mental health service for young children placed in foster care due to abuse and neglect.

Despite knowledge about the profound effects of child abuse and neglect, we know little about how best to assess whether maltreated children should return home. The effectiveness of the New Orleans Intervention Model (NIM) is being tested in a randomized controlled trial where the comparison is social work 'services as usual.' The future trial results will tell us which approach produces the best outcomes for children; meanwhile qualitative process evaluation is generating intriguing findings about the perceived impact of NIM on decision-making about childrens' futures. Interviews and focus groups were conducted with social workers, foster carers, legal decision-makers and the NIM team (n=63). Data were analysed thematically. Findings suggest that NIM is seen as bringing greater influence ('clout') to decision-making due to its depth of focus, provision of treatment for the family, health professional input and perceived objectivity. Simultaneously, the NIM approach and the detailed information it produces potentially throws judgments into doubt in the legal system. Clout/doubt perceptions permeate opinions about NIM and are inter-related with a historical discourse about 'health versus social' models of information gathering, with implications for assessment of child abuse and neglect that extend beyond the study context. The juxtaposition of 'clout versus doubt' both highlights and is strengthened by an intense focus among social workers and legal professionals on how evidence will be regarded within legal fora when making decisions about children. There is continuing uncertainty in the child welfare system about the best ways of assessing maltreated children, underscoring a continued need for the trial.

Education programmes preparing independent prescribers in Scotland: an evaluation.

BACKGROUND: Nurse prescribing (NP) is part of the modernisation of the health care workforce and contributes to patient care by improving access to quality services and medication, through utilisation of advanced professional skills. Nurses and midwives need to complete additional education in order to prescribe. This paper explores pedagogical issues relevant to professional training programmes. OBJECTIVES: To assess if programmes of education for nurse prescribing in Scotland were fit for purpose, from both the student and educator perspective with recommendations for future educational delivery. DESIGN: Data were collected using several methods: a questionnaire to all course members on prescribing programmes followed by focus-groups; and interviews with programme providers. RESULTS: Nurses and midwives training as prescribers work in a wide range of healthcare settings, in different geographic environments. They tended to be experienced, educated to degree level and most are over forty years of age. Most undertook the course to develop professionally and to improve patient care. Existing provision of education for prescribing is deemed appropriate and fit for purpose. The NP programme greatly enhances pharmacological knowledge building on existing clinical experience. The nature of these programmes works well and should be retained. However, whilst the educational programmes were centrally funded, less than half of students were provided with any allocated study time from their employers preventing nurses from maximising the gain from the educational preparation for prescribing. CONCLUSIONS: Nurse and midwife generic preparation for independent nurse prescribing in Scotland greatly increases professional expertise and is appropriate and fit for purpose. As other countries beyond Scotland and the UK seek to further progress nursing roles, learning from this controlled and structured development of prescribing underpinned by evidence could be of significant benefit.