Lapatinib plus Capecitabine versus Trastuzumab plus Capecitabine in the Treatment of Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer with Central Nervous System Metastases for Patients Currently or Previously Treated with Trastuzumab (LANTERN): a Phase II Randomised Trial.

AIMS: Brain (central nervous system; CNS) metastases occur in 30-50% of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). A substantive evidence base for treatment is lacking, but activity with lapatinib plus capecitabine (lap-cap) has been reported. We compared lap-cap with trastuzumab plus capecitabine (tras-cap) in patients with HER2-positive MBC with CNS metastases previously treated with trastuzumab. MATERIALS AND METHODS: This open-label randomised phase II screening trial aimed to randomise 130 participants over 2 years to receive lap-cap or tras-cap. Eligible patients had HER2-positive MBC with newly diagnosed or recently progressed CNS metastases; previous, or current, treatment included: trastuzumab, a taxane or anthracycline and recent completion of local cranial therapy. The primary end point was time to progression of CNS metastases within the 24-week trial period. Secondary objectives included CNS response rate, progression-free survival, steroid use for CNS symptoms and feasibility of recruitment to a large phase III trial. RESULTS: Between September 2011 and October 2013, 30 participants were randomised, 16 to lap-cap and 14 to tras-cap. Recruitment to a large phase III trial was determined not to be feasible. At 24 weeks, CNS disease progression was 41.8% (95% confidence interval 16.1-67.5%) in lap-cap and 41.2% (95% confidence interval 12.8-69.6%) in tras-cap arms; progression-free survival was 44.4% (95% confidence interval 18.1-70.8%) in lap-cap and 50.0% (95% confidence interval 20.9-79.1%) in tras-cap arms. CONCLUSION: Poor recruitment confirmed that a larger phase III trial would not be feasible and prohibited a preliminary evaluation of the superiority of lap-cap over tras-cap. Descriptive statistics are presented to inform the limited evidence base and future study design.

Longer-term effectiveness of systemic family therapy compared with treatment as usual for young people after self-harm: An extended follow up of pragmatic randomised controlled trial.

BACKGROUND: Self-harm in adolescents is common and repetition frequent. Evidence for effective interventions to reduce self-harm is limited. Long term follow-up of existing studies is rare. METHODS: Extended follow up, from 18 to at least 36-months, of the SHIFT trial: a pragmatic, multi-centre, individually-randomised, controlled trial involving young people (11-17) who had self-harmed at least twice and presented to Child & Adolescent Mental Health Services (CAMHS). SHIFT evaluated manualised family therapy (FT) versus treatment as usual (TAU) in reducing repetition of self-harm leading to hospital attendance 18 months post-randomisation.We obtained ONS mortality data, adult mental health data, and further details of hospital attendance from routine Hospital Episode Statistics (HES) data plus researcher follow-up. We assessed longer-term differences in outcome using multivariable Cox Proportional Hazards regression analysis, and assessed all-cause mortality and morbidity relating to hospital attendances for reasons other than self-harm. STUDY REGISTRATION: ISRCTN 59793150. OUTCOMES: The original sample of 832 were randomised between April 2010 and December 2013. Extended follow-up continued until February 2017 for a median 55·4 months (range 0-82·5 months), providing post 18-month data for 804 (96·6%) participants, of whom 785 (94·4%) had a minimum of 36-months follow-up.There was no evidence of a between-group difference in the primary outcome during the extended follow-up period (Hazard Ratio (HR) 1·03; 95% CI: 0·83, 1·28; p-value=0·78), consistent with our findings in the original trial with 18 months follow-up (HR 1·14, 95% CI 0·87, 1·49; p-value 0·33). There was a reduced rate of self-harm in older participants aged 15-17 (HR 0·7, 95% CI 0·56, 0·88), as compared with those aged 11-14; and significantly increased rates of self-harm in participants whose index episode combined self-injury and poisoning (HR 1·8, 95% CI 1·2, 2·7). Two deaths were reported during the extended follow up period. INTERPRETATION: For adolescents referred to CAMHS after self-harm, having self-harmed at least once before, trial FT confers no benefits over TAU in reducing subsequent hospitalisation for self-harm over 18 months or 36 months. FUNDING: NIHR HTA Reference: 07/33/01.

The feasibility of using the EQ-5D-3L with adults with mild to moderate learning disabilities within a randomized control trial: a qualitative evaluation.

BACKGROUND: In trials incorporating a health economic evaluation component, reliable validated measures for health-related quality of life (HRQOL) are essential. The EQ-5D is the preferred measure for cost-effectiveness analysis in UK trials. This paper presents a qualitative evaluation of the use of the EQ-5D-3L in a feasibility randomised control trial with participants who had a mild- to  moderate learning disability and type 2 diabetes. METHODS: Researchers administered the EQ-5D-3L to 82 participants at baseline and 77 at follow-up. After each interview, researchers rated the ease of administering the EQ-5D-3L and made free-text entries on the administration experience. For a subset of 16 interviews, researchers audio-recorded more detailed journal entries. Ease of administration data were analysed using descriptive statistics. Free-text responses were subject to a basic content analysis. The EQ-5D-3L-related journal entries were transcribed, coded and analysed thematically. RESULTS: Over half of participants were perceived to experience difficulty answering some or all of the items in the EQ-5D-3L (60% at baseline; 54% at follow-up). Analysis of the free-text entries and audio journals identified four themes that question the use of the EQ-5D-3L in this population. The first theme is related to observations of participant intellectual ability and difficulties, for example, in understanding the wording of the measure. Theme 2 is related to the normalisation of adjustments for impairments, which rendered the measure less sensitive in this population. Theme 3 is related to researcher adaptation and non-standard administration. An overarching fourth theme was identified in that people with learning disabilities were viewed as 'unreliable witnesses' by both researchers and supporters. CONCLUSIONS: It is recommended that the EQ-5D-3L should not be used in isolation to assess health-related quality of life outcomes in trials research in adults with a learning disability. Further research is required to develop and evaluate a version of the EQ-5D appropriate for this population in trials research. It is unrealistic to expect that adjustments to the wording alone will deliver an appropriate measure: supporter or researcher involvement will almost always be required. This requirement needs to be factored into the development and administration guidelines of any new version of the EQ-5D for adults with a learning disability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41897033 [registered 21 January 2013].

Randomized controlled feasibility trial of supported self-management in adults with Type 2 diabetes mellitus and an intellectual disability: OK Diabetes.

AIMS: To undertake a feasibility randomized controlled trial of supported self-management vs treatment as usual in a population of adults with obesity, Type 2 diabetes and an intellectual disability. METHODS: We conducted an individually randomized feasibility trial. Participants were adults aged >18 years with a mild or moderate intellectual disability, living in the community with Type 2 diabetes, on any therapy other than insulin. Participants had mental capacity to consent to research and the intervention. Inclusion criteria included HbA1c > 48 mmol/mol (6.5%), BMI >25 kg/m2 , or self-reported physical activity below national guideline levels. The experimental intervention was standardized supported self-management delivered by diabetes specialist nurses plus treatment as usual, compared with treatment as usual alone. Feasibility outcomes included: recruitment and retention; intervention acceptability and feasibility; data collection and completeness for physiological state and values for candidate primary outcomes (HbA1c and BMI). RESULTS: A total of 82 participants (89% of those contacted and eligible) were randomized. All supported self-management sessions were completed by 35/41 participants (85%); only four completed no sessions. Data on the follow-up candidate primary outcomes HbA1c and BMI were obtained for 75/82 (91%) and 77/82 participants (94%), respectively. The mean baseline HbA1c was 56±16.5 mmol/mol (7.3±1.5%) and the mean BMI was 34±7.6 kg/m2 . CONCLUSIONS: Adherence to supported self-management and willingness to have blood taken for outcome measurement was good. A definitive randomized controlled trial is feasible in this population. (Trial registration: Current Controlled Trials ISRCTN41897033).

Characterizing adults with Type 2 diabetes mellitus and intellectual disability: outcomes of a case-finding study.

AIMS: To report the results of a case-finding study conducted during a feasibility trial of a supported self-management intervention for adults with mild to moderate intellectual disability and Type 2 diabetes mellitus, and to characterize the study sample in terms of diabetes control, health, and access to diabetes management services and support. METHODS: We conducted a cross-sectional case-finding study in the UK (March 2013 to June 2015), which recruited participants mainly through primary care settings. Data were obtained from medical records and during home visits. RESULTS: Of the 325 referrals, 147 eligible individuals participated. The participants' mean (sd) HbA1c concentration was 55 (15) mmol/mol [7.1 (1.4)%] and the mean (sd) BMI was 32.9 (7.9) kg/m2 , with 20% of participants having a BMI >40 kg/m2 . Self-reported frequency of physical activity was low and 79% of participants reported comorbidity, for example, cardiovascular disease, in addition to Type 2 diabetes. The majority of participants (88%) had a formal or informal supporter involved in their diabetes care, but level and consistency of support varied greatly. Post hoc exploratory analyses showed a significant association between BMI and self-reported mood, satisfaction with diet and weight. CONCLUSIONS: We found high obesity and low physical activity levels in people with intellectual disability and Type 2 diabetes. Glycaemic control was no worse than in the general Type 2 diabetes population. Increased risk of morbidity in this population is less likely to be attributable to poor glycaemic control and is probably related, at least in part, to greater prevalence of obesity and inactivity. More research, focused on weight management and increasing activity in this population, is warranted.

Prognosis of the infected diabetic foot ulcer: a 12-month prospective observational study.

AIMS: To determine clinical outcomes and explore prognostic factors related to ulcer healing in people with a clinically infected diabetic foot ulcer. METHODS: This multicentre, prospective, observational study reviewed participants' data at 12 months after culture of a diabetic foot ulcer requiring antibiotic therapy. From participants' notes, we obtained information on the incidence of wound healing, ulcer recurrence, lower extremity amputation, lower extremity revascularization and death. We estimated the cumulative incidence of healing at 6 and 12 months, adjusted for lower extremity amputation and death using a competing risk analysis, and explored the relationship between baseline factors and healing incidence. RESULTS: In the first year after culture of the index ulcer, 45/299 participants (15.1%) had died. The ulcer had healed in 136 participants (45.5%), but recurred in 13 (9.6%). An ipsilateral lower extremity amputation was recorded in 52 (17.4%) and revascularization surgery in 18 participants (6.0%). Participants with an ulcer present for ~2 months or more had a lower incidence of healing (hazard ratio 0.55, 95% CI 0.39 to 0.77), as did those with a PEDIS (perfusion, extent, depth, infection, sensation) perfusion grade of ≥2 (hazard ratio 0.37, 95% CI 0.25 to 0.55). Participants with a single ulcer on their index foot had a higher incidence of healing than those with multiple ulcers (hazard ratio 1.90, 95% CI 1.18 to 3.06). CONCLUSIONS: Clinical outcomes at 12 months for people with an infected diabetic foot ulcer are generally poor. Our data confirm the adverse prognostic effect of limb ischaemia, longer ulcer duration and the presence of multiple ulcers.