Diane Whitham

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial

Summary Background Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. Findings Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001. Interpretation Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Funding NIHR Health Technology Assessment Programme.

A randomized controlled trial to compare the safety and effectiveness of doxycycline (200 mg daily) with oral prednisolone (0.5 mg kg(-1) daily) for initial treatment of bullous pemphigoid: a protocol for the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) Trial.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease in older people, and is associated with significant morbidity and mortality. Oral corticosteroids are usually effective but the side‐effects are thought to contribute to the high morbidity and mortality rate. Treatment with oral tetracyclines may be effective but high‐quality, randomized controlled trials (RCTs) are needed to confirm this.

The addition of a goal-based motivational interview to treatment as usual to enhance engagement and reduce dropouts in a personality disorder treatment service: results of a feasibility study for a randomized controlled trial

BackgroundThere are high rates of treatment non-completion for personality disorder and those who do not complete treatment have poorer outcomes. A goal-based motivational interview may increase service users’ readiness to engage with therapy and so enhance treatment retention. We conducted a feasibility study to inform the design of a randomized controlled trial. The aims were to test the feasibility of recruitment, randomization and follow-up, and to conduct a preliminary evaluation of the effectiveness of the motivational interview.MethodsPatients in an outpatient personality disorder service were randomized to receive the Personal Concerns Inventory plus treatment as usual or treatment as usual only. The main randomized controlled trial feasibility criteria were recruitment of 54% of referrals, and 80% of clients and therapists finding the intervention acceptable. Information was collected on treatment attendance, the clarity of therapy goals and treatment engagement.ResultsThe recruitment rate was 29% (76 of 258). Of 12 interviewed at follow-up, eight (67%) were positive about the Personal Concerns Inventory. Pre-intervention interviews were conducted with 61% (23 out of 38) of the Personal Concerns Inventory group and 74% (28 out of 38) of the treatment as usual group. Participants’ therapy goals were blind-rated for clarity on a scale of 0 to 10. The mean score for the Personal Concerns Inventory group was 6.64 (SD = 2.28) and for the treatment as usual group 2.94 (SD = 1.71). Over 12 weeks, the median percentage session attendance was 83.33% for the Personal Concerns Inventory group (N = 17) and 66.67% for the treatment as usual group (N = 24). Of 59 eligible participants at follow-up, the Treatment Engagement Rating scale was completed for 40 (68%). The mean Treatment Engagement Rating scale score for the Personal Concerns Inventory group was 6.64 (SD = 2.28) and for the treatment as usual group 2.94 (SD = 1.71). Of the 76 participants, 63 (83%) completed the Client Service Receipt Inventory at baseline and 34 of 59 (58%) at follow-up.ConclusionShortfalls in recruitment and follow-up data collection were explained by major changes to the service. However, evidence of a substantial positive impact of the Personal Concerns Inventory on treatment attendance, clarity of therapy goals and treatment engagement, make a full-scale evaluation worth pursuing. Further preparatory work is required for a multisite trial.Trial registrationClinicalTrials.Gov.UK Identifier - NCT01132976

Feasibility and Preliminary Efficacy of Visual Cue Training to Improve Adaptability of Walking after Stroke: Multi-Centre, Single-Blind Randomised Control Pilot Trial

Objectives Given the importance of vision in the control of walking and evidence indicating varied practice of walking improves mobility outcomes, this study sought to examine the feasibility and preliminary efficacy of varied walking practice in response to visual cues, for the rehabilitation of walking following stroke. Design This 3 arm parallel, multi-centre, assessor blind, randomised control trial was conducted within outpatient neurorehabilitation services Participants Community dwelling stroke survivors with walking speed <0.8m/s, lower limb paresis and no severe visual impairments Intervention Over-ground visual cue training (O-VCT), Treadmill based visual cue training (T-VCT), and Usual care (UC) delivered by physiotherapists twice weekly for 8 weeks. Main outcome measures: Participants were randomised using computer generated random permutated balanced blocks of randomly varying size. Recruitment, retention, adherence, adverse events and mobility and balance were measured before randomisation, post-intervention and at four weeks follow-up. Results Fifty-six participants participated (18 T-VCT, 19 O-VCT, 19 UC). Thirty-four completed treatment and follow-up assessments. Of the participants that completed, adherence was good with 16 treatments provided over (median of) 8.4, 7.5 and 9 weeks for T-VCT, O-VCT and UC respectively. No adverse events were reported. Post-treatment improvements in walking speed, symmetry, balance and functional mobility were seen in all treatment arms. Conclusions Outpatient based treadmill and over-ground walking adaptability practice using visual cues are feasible and may improve mobility and balance. Future studies should continue a carefully phased approach using identified methods to improve retention. Trial Registration Clinicaltrials.gov NCT01600391

Visual cue training to improve walking and turning after stroke: a study protocol for a multi-centre, single blind randomised pilot trial

BackgroundVisual information comprises one of the most salient sources of information used to control walking and the dependence on vision to maintain dynamic stability increases following a stroke. We hypothesize, therefore, that rehabilitation efforts incorporating visual cues may be effective in triggering recovery and adaptability of gait following stroke. This feasibility trial aims to estimate probable recruitment rate, effect size, treatment adherence and response to gait training with visual cues in contrast to conventional overground walking practice following stroke.Methods/designA 3-arm, parallel group, multi-centre, single blind, randomised control feasibility trial will compare overground visual cue training (O-VCT), treadmill visual cue training (T-VCT), and usual care (UC). Participants (n = 60) will be randomly assigned to one of three treatments by a central randomisation centre using computer generated tables to allocate treatment groups. The research assessor will remain blind to allocation. Treatment, delivered by physiotherapists, will be twice weekly for 8 weeks at participating outpatient hospital sites for the O-VCT or UC and in a University setting for T-VCT participants.Individuals with gait impairment due to stroke, with restricted community ambulation (gait speed <0.8m/s), residual lower limb paresis and who are able to take part in repetitive walking practice involving visual cues (i.e., no severe visual impairments, able to walk with minimal assistance and no comorbid medical contraindications for walking practice) will be included.The primary outcomes concerning participant enrolment, recruitment, retention, and health and social care resource use data will be recorded over a recruitment period of 18 months. Secondary outcome measures will be undertaken before randomisation (baseline), after the eight-week intervention (outcome), and at three months (follow-up). Outcome measures will include gait speed and step length symmetry; time and steps taken to complete a 180° turn; assessment of gait adaptability (success rate in target stepping); timed up and go; Fugl-Meyer lower limb motor assessment; Berg balance scale; falls efficacy scale; SF-12; and functional ambulation category.DiscussionParticipation and compliance measured by treatment logs, accrual rate, attrition, and response variation will determine sample sizes for an early phase randomised controlled trial and indicate whether a definitive late phase efficacy trial is justified.Trial registrationClinicaltrials.gov, NCT01600391.

The addition of a goal-based motivational interview to standardised treatment as usual to reduce dropouts in a service for patients with personality disorder: a feasibility study

BackgroundRates of non-completion of treatments for personality disorder are high and there are indications that those who do not complete treatment have worse outcomes than those who do. Improving both cost-efficiency and client welfare require attention to engaging people with personality disorder in treatment. A motivational interview, based on the Personal Concerns Inventory, may have the ability to enhance engagement and retention in therapy. Here, we report the protocol for a feasibility study for a randomised controlled trial (RCT).MethodsAll referrals accepted to the psychological service of Nottinghamshire Healthcare NHS Trusts outpatient service for people with personality disorder are eligible for inclusion. Consenting participants are randomised to receive the Personal Concerns Inventory interview plus treatment as usual or treatment as usual only. We aim to recruit 100 participants over 11/2 years. A randomised controlled trial will be considered feasible if [1] the recruitment rate to the project is 54% of all referrals (95% CI 54-64), [2] 80% of clients find the intervention acceptable in terms of its practicability and usefulness (95% CI 80-91), and [3] 80% of therapists report finding the intervention helpful (95% CI 80-100). In a full-scale randomised controlled trial, the primary outcome measure will be completion of treatment i.e., entry into and completion of ≥ 75% of sessions offered. Therefore, information will be collected on recruitment rates, attendance at therapy sessions, and completion of treatment. The feasibility of examining the processes of engagement will be tested by assessing the value, coherence, and attainability of goals pre-treatment, and engagement in treatment. The costs associated with the intervention will be calculated, and the feasibility of calculating the cost-benefits of the intervention will be tested. The views of clients and therapists on the intervention, collected using semi-structured interviews, will be analysed using thematic analysis.DiscussionThe Personal Concerns Interview as a preparation for treatment of people with personality has the potential to maximise treatment uptake, reduce unfilled places in treatment programmes, and prevent group treatments faltering through non-attendance. Most importantly, it has the potential to improve patient outcomes, helping them to function better and reduce hospitalisation.Trial RegistrationClinicalTrials.Gov.UK Identifier - NCT01132976

A randomised controlled trial to compare the safety, effectiveness and cost-effectiveness of doxycycline (200 mg/day) with that of oral prednisolone (0.5 mg/kg/day) for initial treatment of bullous pemphigoid: the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) trial

BACKGROUND Bullous pemphigoid (BP) is an autoimmune blistering skin disorder with increased morbidity and mortality in the elderly. OBJECTIVES To evaluate the effectiveness, safety and cost-effectiveness of a strategy of initiating BP treatment with oral doxycycline or oral prednisolone. We hypothesised that starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral prednisolone. DESIGN Pragmatic multicentre two-armed parallel-group randomised controlled trial with an economic evaluation. SETTING A total of 54 dermatology secondary care centres in the UK and seven in Germany. PARTICIPANTS Adults with BP [three or more blisters at two sites and positive direct and/or indirect immunofluorescence (immunoglobulin G and/or complement component 3 immunofluorescence at the dermal-epidermal junction)] and able to give informed consent. INTERVENTIONS Participants were allocated using online randomisation to initial doxycycline treatment (200 mg/day) or prednisolone (0.5 mg/kg/day). Up to 30 g/week of potent topical corticosteroids was permitted for weeks 1-3. After 6 weeks, clinicians could switch treatments or alter the prednisolone dose as per normal practice. MAIN OUTCOME MEASURES Primary outcomes: (1) the proportion of participants with three or fewer blisters at 6 weeks (investigator blinded) and (2) the proportion with severe, life-threatening and fatal treatment-related events at 52 weeks. A regression model was used in the analysis adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Secondary outcomes included the effectiveness of blister control after 6 weeks, relapses, related adverse events and quality of life. The economic evaluation involved bivariate regression of costs and quality-adjusted life-years (QALYs) from a NHS perspective. RESULTS In total, 132 patients were randomised to doxycycline and 121 to prednisolone. The mean patient age was 77.7 years and baseline severity was as follows: mild 31.6% (three to nine blisters), moderate 39.1% (10-30 blisters) and severe 29.3% (> 30 blisters). For those starting on doxycycline, 83 out of 112 (74.1%) had three or fewer blisters at 6 weeks, whereas for those starting on prednisolone 92 out of 101 (91.1%) had three or fewer blisters at 6 weeks, an adjusted difference of 18.6% in favour of prednisolone [90% confidence interval (CI) 11.1% to 26.1%], using a modified intention-to-treat (mITT) analysis. Per-protocol analysis showed similar results: 74.4% compared with 92.3%, an adjusted difference of 18.7% (90% CI 9.8% to 27.6%). The rate of related severe, life-threatening and fatal events at 52 weeks was 18.2% for those started on doxycycline and 36.6% for those started on prednisolone (mITT analysis), an adjusted difference of 19.0% (95% CI 7.9% to 30.1%; p = 0.001) in favour of doxycycline. Secondary outcomes showed consistent findings. There was no significant difference in costs or QALYs per patient at 1 year between doxycycline-initiated therapy and prednisolone-initiated therapy (incremental cost of doxycycline-initiated therapy £959, 95% CI -£24 to £1941; incremental QALYs of doxycycline-initiated therapy -0.024, 95% CI -0.088 to 0.041). Using a willingness-to-pay criterion of < £20,000 per QALY gained, the net monetary benefit associated with doxycycline-initiated therapy was negative but imprecise (-£1432, 95% CI -£3094 to £230). CONCLUSIONS A strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and considerably safer in the long term. The limitations of the trial were the wide non-inferiority margin, the moderate dropout rate and that serious adverse event collection was unblinded. Future work might include inducing remission with topical or oral corticosteroids and then randomising to doxycycline or prednisolone for maintenance. TRIAL REGISTRATION Current Controlled Trials ISRCTN13704604. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 10. See the NIHR Journals Library website for further project information.

Psycho-education with problem solving (PEPS) therapy for adults with personality disorder: A pragmatic multi-site community-based randomised clinical trial

BackgroundImpairment in social functioning is a key component of personality disorder. Therefore psycho-education and problem solving (PEPS) therapy may benefit people with this disorder. Psycho-education aims to educate, build rapport, and motivate people for problem solving therapy. Problem solving therapy aims to help clients solve interpersonal problems positively and rationally, thereby improving social functioning and reducing distress. PEPS therapy has been evaluated with community adults with personality disorder in an exploratory trial. At the end of treatment, compared to a wait-list control group, those treated with PEPS therapy showed better social functioning, as measured by the Social Functioning Questionnaire (SFQ). A definitive evaluation is now being conducted to determine whether PEPS therapy is a clinically and cost-effective treatment for people with personality disorderMethodsThis is a pragmatic, two-arm, multi-centre, parallel, randomised controlled clinical trial. The target population is community-dwelling adults with one or more personality disorder, as identified by the International Personality Disorder Examination (IPDE). Inclusion criteria are: Living in the community (including residential or supported care settings); presence of one or more personality disorder; aged 18 or over; proficiency in spoken English; capacity to provide informed consent. Exclusion criteria are: Primary diagnosis of a functional psychosis; insufficient degree of literacy, comprehension or attention to be able to engage in trial therapy and assessments; currently engaged in a specific programme of psychological treatment for personality disorder or likely to start such treatment during the trial period; currently enrolled in any other trial. Suitable participants are randomly allocated to PEPS therapy plus treatment as usual (TAU) or TAU only. We aim to recruit 340 men and women. The primary outcome is social functioning as measured by the SFQ. A reduction (i.e., an improvement) of 2 points or more on the SFQ at follow-up 72 weeks post-randomisation is our pre-specified index of clinically significant change. Secondary outcomes include a reduction of unscheduled service usage and an increase in scheduled service usage; improved quality of life; and a reduction in mental distress.DiscussionPEPS therapy has potential as an economical, accessible, and acceptable intervention for people with personality disorder. The results from this randomised controlled trial will tell us if PEPS therapy is effective and cost-effective. If so, then it will be a useful treatment for inclusion in a broader menu of treatment options for this group of service users.Trial RegistrationInternational Standard Randomised Controlled Trial Number - ISRCTN70660936

Doxycycline compared to prednisolone therapy for patients with bullous pemphigoid: cost-effectiveness analysis of the BLISTER trial

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with significant morbidity and mortality. Doxycycline and prednisolone to treat bullous pemphigoid were compared within a randomized controlled trial (RCT).

Psychoeducation and Problem Solving (PEPS) Therapy for Adults With Personality Disorder: A Pragmatic Randomized-Controlled Trial

We compared psychoeducation and problem solving (PEPS) therapy against usual treatment in a multisite randomized-controlled trial. The primary outcome was social functioning. We aimed to recruit 444 community-dwelling adults with personality disorder; however, safety concerns led to an early cessation of recruitment. A total of 154 people were randomized to PEPS and 152 to usual treatment. Follow-up at 72 weeks was completed for 68%. PEPS therapy was no more effective than usual treatment for improving social functioning (adjusted difference in mean Social Functioning Questionnaire scores = -0.73; 95% CI [-1.83, 0.38]; p = 0.19). PEPS therapy is not an effective treatment for improving social functioning of adults with personality disorder living in the community.