The treatment of child anxiety disorders via guided parent-delivered cognitive-behavioural therapy: a randomised controlled trial

Background Promising evidence has emerged of clinical gains using guided self-help cognitive-behavioural therapy (CBT) for child anxiety and by involving parents in treatment; however, the efficacy of guided parent-delivered CBT has not been systematically evaluated in UK primary and secondary settings. Aims To evaluate the efficacy of low-intensity guided parent-delivered CBT treatments for children with anxiety disorders. Method A total of 194 children presenting with a current anxiety disorder, whose primary carer did not meet criteria for a current anxiety disorder, were randomly allocated to full guided parent-delivered CBT (four face-to-face and four telephone sessions) or brief guided parent-delivered CBT (two face-to-face and two telephone sessions), or a wait-list control group (trial registration: ISRCTN92977593). Presence and severity of child primary anxiety disorder (Anxiety Disorders Interview Schedule for DSM-IV, child/parent versions), improvement in child presentation of anxiety (Clinical Global Impression-Improvement scale), and change in child anxiety symptoms (Spence Children’s Anxiety Scale, child/parent version and Child Anxiety Impact scale, parent version) were assessed at post-treatment and for those in the two active treatment groups, 6 months post-treatment. Results Full guided parent-delivered CBT produced superior diagnostic outcomes compared with wait-list at post-treatment, whereas brief guided parent-delivered CBT did not: at post-treatment, 25 (50%) of those in the full guided CBT group had recovered from their primary diagnosis, compared with 16 (25%) of those on the wait-list (relative risk (RR) 1.85, 95% CI 1.14-2.99); and in the brief guided CBT group, 18 participants (39%) had recovered from their primary diagnosis post-treatment (RR = 1.56, 95% CI 0.89-2.74). Level of therapist training and experience was unrelated to child outcome. Conclusions Full guided parent-delivered CBT is an effective and inexpensive first-line

Transient heparin-induced platelet activation linked to generation of platelet 12-lipoxygenase: findings from a randomised controlled trial

Previously we demonstrated that heparin administration during carotid endarterectomy (CEA) caused a marked, but transient increase in platelet aggregation to arachidonic acid (AA) and adenosine diphosphate (ADP), despite effective platelet cyclo-oxygenase-1 (COX-1) inhibition with aspirin. Here we investigated the metabolism of AA via platelet 12-lipoxygenase (12-LOX) as a possible mediator of the observed transient aspirin resistance, and compared the effects of unfractionated (UFH) and low-molecular-weight (LMWH) heparin. A total of 43 aspirinated patients undergoing CEA were randomised in the trial to 5,000 IU UFH (n=22) or 2,500 IU LMWH (dalteparin, n=21). Platelet aggregation to AA (4x10⁻³) and ADP (3x10⁻⁶) was determined, and the products of the COX-1 and 12-LOX pathways; thromboxane B₂ (TXB₂) and 12-hydroxyeicosatretraenoic acid (12-HETE) were measured in plasma, and in material released from aggregating platelets.Aggregation to AA increased significantly (~10-fold) following heparinisation (p<0.0001), irrespective of heparin type (p=0.33). Significant, but smaller (~2-fold) increases in aggregation to ADP were also seen, which were significantly lower in the platelets of patients randomised to LMWH (p<0.0001). Plasma levels of TxB2 did not rise following heparinisation (p=0.93), but 12-HETE increased significantly in the patients' plasma, and released from platelets stimulated in vitro withADP, with both heparin types (p<0.0001). The magnitude of aggregation to ADP correlated with 12-HETE generation (p=0.03). Heparin administration during CEA generates AA that is metabolised to 12-HETE via the 12-LOX pathway, possibly explaining the phenomenon of transient heparin-induced platelet activation. LMWH has less effect on aggregation and 12-HETE generation than UFH when the platelets are stimulated with ADP.

Design and baseline characteristics of the Food4Me study: a web-based randomised controlled trial of personalised nutrition in seven European countries

Improving lifestyle behaviours has considerable potential for reducing the global burden of non-communicable diseases, promoting better health across the life-course and increasing well-being. However, realising this potential will require the development, testing and implementation of much more effective behaviour change interventions than are used conventionally. Therefore, the aim of this study was to conduct a multi-centre, web-based, proof-of-principle study of personalised nutrition (PN) to determine whether providing more personalised dietary advice leads to greater improvements in eating patterns and health outcomes compared to conventional population-based advice. A total of 5,562 volunteers were screened across seven European countries; the first 1,607 participants who fulfilled the inclusion criteria were recruited into the trial. Participants were randomly assigned to one of the following intervention groups for a 6-month period: Level 0-control group-receiving conventional, non-PN advice; Level 1-receiving PN advice based on dietary intake data alone; Level 2-receiving PN advice based on dietary intake and phenotypic data; and Level 3-receiving PN advice based on dietary intake, phenotypic and genotypic data. A total of 1,607 participants had a mean age of 39.8 years (ranging from 18 to 79 years). Of these participants, 60.9 % were women and 96.7 % were from white-European background. The mean BMI for all randomised participants was 25.5 kg m(-2), and 44.8 % of the participants had a BMI ≥ 25.0 kg m(-2). Food4Me is the first large multi-centre RCT of web-based PN. The main outcomes from the Food4Me study will be submitted for publication during 2015.

A randomised controlled trial of positive memory training for the treatment of depression within schizophrenia

Abstract Background: Depression is highly prevalent within individuals diagnosed with schizophrenia, and is associated with an increased risk of suicide. There are no current evidence based treatments for low mood within this group. The specific targeting of co-morbid conditions within complex mental health problems lends itself to the development of short-term structured interventions which are relatively easy to disseminate within health services. A brief cognitive intervention based on a competitive memory theory of depression, is being evaluated in terms of its effectiveness in reducing depression within this group. Methods/Design: This is a single blind, intention-to-treat, multi-site, randomized controlled trial comparing Positive Memory Training plus Treatment as Usual with Treatment as Usual alone. Participants will be recruited from two NHS Trusts in Southern England. In order to be eligible, participants must have a DSM-V diagnosis of schizophrenia or schizo-affective disorder and exhibit at least a mild level of depression. Following baseline assessment eligible participants will be randomly allocated to either the Positive Memory Training plus Treatment as Usual group or the Treatment as Usual group. Outcome will be assessed at the end of treatment (3-months) and at 6-month and 9-month post randomization by assessors blind to group allocation. The primary outcome will be levels of depression and secondary outcomes will be severity of psychotic symptoms and cost-effectiveness. Semi-structured interviews will be conducted with all participants who are allocated to the treatment group so as to explore the acceptability of the intervention. Discussion: Cognitive behaviour therapy is recommended for individuals diagnosed with schizophrenia. However, the number of sessions and length of training required to deliver this intervention has caused a limit in availability. The current trial will evaluate a short-term structured protocol which targets a co-morbid condition often considered of primary importance by service users. If successful the intervention will be an important addition to current initiatives aimed at increasing access to psychological therapies for people diagnosed with severe mental health problems. Trial registration: Current Controlled Trials. ISRCTN99485756. Registered 13 March 2014.

Treatment of child anxiety in the context of maternal anxiety disorder: a randomised controlled trial and economic analysis

Background Cognitive–behavioural therapy (CBT) for childhood anxiety disorders is associated with modest outcomes in the context of parental anxiety disorder. Objectives This study evaluated whether or not the outcome of CBT for children with anxiety disorders in the context of maternal anxiety disorders is improved by the addition of (i) treatment of maternal anxiety disorders, or (ii) treatment focused on maternal responses. The incremental cost-effectiveness of the additional treatments was also evaluated. Design Participants were randomised to receive (i) child cognitive–behavioural therapy (CCBT); (ii) CCBT with CBT to target maternal anxiety disorders [CCBT + maternal cognitive–behavioural therapy (MCBT)]; or (iii) CCBT with an intervention to target mother–child interactions (MCIs) (CCBT + MCI). Setting A NHS university clinic in Berkshire, UK. Participants Two hundred and eleven children with a primary anxiety disorder, whose mothers also had an anxiety disorder. Interventions All families received eight sessions of individual CCBT. Mothers in the CCBT + MCBT arm also received eight sessions of CBT targeting their own anxiety disorders. Mothers in the MCI arm received 10 sessions targeting maternal parenting cognitions and behaviours. Non-specific interventions were delivered to balance groups for therapist contact. Main outcome measures Primary clinical outcomes were the child’s primary anxiety disorder status and degree of improvement at the end of treatment. Follow-up assessments were conducted at 6 and 12 months. Outcomes in the economic analyses were identified and measured using estimated quality-adjusted life-years (QALYs). QALYS were combined with treatment, health and social care costs and presented within an incremental cost–utility analysis framework with associated uncertainty. Results MCBT was associated with significant short-term improvement in maternal anxiety; however, after children had received CCBT, group differences were no longer apparent. CCBT + MCI was associated with a reduction in maternal overinvolvement and more confident expectations of the child. However, neither CCBT + MCBT nor CCBT + MCI conferred a significant post-treatment benefit over CCBT in terms of child anxiety disorder diagnoses [adjusted risk ratio (RR) 1.18, 95% confidence interval (CI) 0.87 to 1.62, p = 0.29; adjusted RR CCBT + MCI vs. control: adjusted RR 1.22, 95% CI 0.90 to 1.67, p = 0.20, respectively] or global improvement ratings (adjusted RR 1.25, 95% CI 1.00 to 1.59, p = 0.05; adjusted RR 1.20, 95% CI 0.95 to 1.53, p = 0.13). CCBT + MCI outperformed CCBT on some secondary outcome measures. Furthermore, primary economic analyses suggested that, at commonly accepted thresholds of cost-effectiveness, the probability that CCBT + MCI will be cost-effective in comparison with CCBT (plus non-specific interventions) is about 75%. Conclusions Good outcomes were achieved for children and their mothers across treatment conditions. There was no evidence of a benefit to child outcome of supplementing CCBT with either intervention focusing on maternal anxiety disorder or maternal cognitions and behaviours. However, supplementing CCBT with treatment that targeted maternal cognitions and behaviours represented a cost-effective use of resources, although the high percentage of missing data on some economic variables is a shortcoming. Future work should consider whether or not effects of the adjunct interventions are enhanced in particular contexts. The economic findings highlight the utility of considering the use of a broad range of services when evaluating interventions with this client group. Trial registration Current Controlled Trials ISRCTN19762288. Funding This trial was funded by the Medical Research Council (MRC) and Berkshire Healthcare Foundation Trust and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership (09/800/17) and will be published in full in Health Technology Assessment; Vol. 19, No. 38.

Obsessive Compulsive Treatment Efficacy Trial (OCTET) comparing the clinical and cost effectiveness of self-managed therapies: study protocol for a randomised controlled trial

Background: UK National Institute of Health and Clinical Excellence guidelines for obsessive compulsive disorder (OCD) specify recommendations for the treatment and management of OCD using a stepped care approach. Steps three to six of this model recommend treatment options for people with OCD that range from low-intensity guided self-help (GSH) to more intensive psychological and pharmacological interventions. Cognitive behavioural therapy (CBT), including exposure and response prevention, is the recommended psychological treatment. However, whilst there is some preliminary evidence that self-managed therapy packages for OCD can be effective, a more robust evidence base of their clinical and cost effectiveness and acceptability is required. Methods/Design: Our proposed study will test two different self-help treatments for OCD: 1) computerised CBT (cCBT) using OCFighter, an internet-delivered OCD treatment package; and 2) GSH using a book. Both treatments will be accompanied by email or telephone support from a mental health professional. We will evaluate the effectiveness, cost and patient and health professional acceptability of the treatments. Discussion: This study will provide more robust evidence of efficacy, cost effectiveness and acceptability of self-help treatments for OCD. If cCBT and/or GSH prove effective, it will provide additional, more accessible treatment options for people with OCD.

Improving mood with psychoanalytic and cognitive therapies (IMPACT): a pragmatic effectiveness superiority trial to investigate whether specialised psychological treatment reduces the risk for relapse in adolescents with moderate to severe unipolar depression: study protocol for a randomised controlled trial

Background Up to 70% of adolescents with moderate to severe unipolar major depression respond to psychological treatment plus Fluoxetine (20-50 mg) with symptom reduction and improved social function reported by 24 weeks after beginning treatment. Around 20% of non responders appear treatment resistant and 30% of responders relapse within 2 years. The specific efficacy of different psychological therapies and the moderators and mediators that influence risk for relapse are unclear. The cost-effectiveness and safety of psychological treatments remain poorly evaluated. Methods/Design Improving Mood with Psychoanalytic and Cognitive Therapies, the IMPACT Study, will determine whether Cognitive Behavioural Therapy or Short Term Psychoanalytic Therapy is superior in reducing relapse compared with Specialist Clinical Care. The study is a multicentre pragmatic effectiveness superiority randomised clinical trial: Cognitive Behavioural Therapy consists of 20 sessions over 30 weeks, Short Term Psychoanalytic Psychotherapy 30 sessions over 30 weeks and Specialist Clinical Care 12 sessions over 20 weeks. We will recruit 540 patients with 180 randomised to each arm. Patients will be reassessed at 6, 12, 36, 52 and 86 weeks. Methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, research assessors independent of treatment team and blind to randomization, analysis by intention to treat, data management using remote data entry, measures of quality assurance, advanced statistical analysis, manualised treatment protocols, checks of adherence and competence of therapists and assessment of cost-effectiveness. We will also determine whether time to recovery and/or relapse are moderated by variations in brain structure and function and selected genetic and hormone biomarkers taken at entry. Discussion The objective of this clinical trial is to determine whether there are specific effects of specialist psychotherapy that reduce relapse in unipolar major depression in adolescents and thereby costs of treatment to society. We also anticipate being able to utilise psychotherapy experience, neuroimaging, genetic and hormone measures to reveal what techniques and their protocols may work best for which patients.

The effect of targeting tolerance of children's negative emotions among anxious parents of children with anxiety disorders: a pilot randomised controlled trial

Following cognitive behavioural therapy for child anxiety a significant minority of children fail to lose their diagnosis status. One potential barrier is high parental anxiety. We designed a pilot RCT to test claims that parental intolerance of the child’s negative emotions may impact treatment outcomes. Parents of 60 children with an anxiety disorder, who were themselves highly anxious, received either brief parent-delivered treatment for child anxiety or the same treatment with strategies specifically targeting parental tolerance of their child’s negative emotions. Consistent with predictions, parental tolerance of the child’s negative emotions significantly improved from pre- to post-treatment. However, there was no evidence to inform the direction of this association as improvements were substantial in both groups. Moreover, while there were significant improvements in child anxiety in both conditions, there was little evidence that this was associated with the improvement in parental tolerance. Nevertheless, findings provide important clinical insight, including that parent-led treatments are appropriate even when the parent is highly anxious and that it may not be necessary to adjust interventions for many families.

Acupuncture with manual and electrical stimulation for labour pain : a longitudinal randomised controlled trial

Background: Acupuncture is commonly used to reduce pain during labour despite contradictory results. The aim of this study is to evaluate the effectiveness of acupuncture with manual stimulation and acupuncture with combined manual and electrical stimulation (electro-acupuncture) compared with standard care in reducing labour pain. Our hypothesis was that both acupuncture stimulation techniques were more effective than standard care, and that electro-acupuncture was most effective.  Methods: A longitudinal randomised controlled trial. The recruitment of participants took place at the admission to the labour ward between November 2008 and October 2011 at two Swedish hospitals. 303 nulliparous women with normal pregnancies were randomised to: 40 minutes of manual acupuncture (MA), electro-acupuncture (EA), or standard care without acupuncture (SC). Primary outcome: labour pain, assessed by Visual Analogue Scale (VAS). Secondary outcomes: relaxation, use of obstetric pain relief during labour and post-partum assessments of labour pain. The sample size calculation was based on the primary outcome and a difference of 15 mm on VAS was regarded as clinically relevant, this gave 101 in each group, including a total of 303 women.  Results: Mean estimated pain scores on VAS (SC: 69.0, MA: 66.4 and EA: 68.5), adjusted for: treatment, age, education, and time from baseline, with no interactions did not differ between the groups (SC vs MA: mean difference 2.6, 95% confidence interval [CI] -1.7-6.9 and SC vs EA: mean difference 0.6 [95% CI] -3.6-4.8). Fewer number of women in the EA group used epidural analgesia (46%) than women in the MA group (61%) and SC group (70%) (EA vs SC: odds ratio [OR] 0.35; [95% CI] 0.19-0.67).  Conclusions: Acupuncture does not reduce women's experience of labour pain, neither with manual stimulation nor with combined manual and electrical stimulation. However, fewer women in the EA group used epidural analgesia thus indicating that the effect of acupuncture with electrical stimulation may be underestimated. These findings were obtained in a context with free access to other forms of pain relief.

A randomised controlled trial of periconal eye blockade with or without ultrasound guidance

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial

Background: Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma. Methods: Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1: 1: 1) to receive FOLFOX4 (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 1; leucovorin 200 mg/m(2) plus fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7.5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7.5 mg/kg plus XELOX (oxaliplatin 130 mg/m(2) on day 1 every 2 weeks plus oral capecitabine 1000 mg/m(2) twice daily on days 1-15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7.5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4-8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918. Findings: Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab-FOLFOX4, and 952 to receive bevacizumab-XELOX. After a median follow-up of 48 months (range 0-66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab-FOLFOX4 group, and 253 (27%) in the bevacizumab-XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1.17 (95% CI 0.98-1.39; p=0.07), and for bevacizumab-XELOX versus FOLFOX4 was 1.07 (0.90-1.28; p=0.44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1.27 (1.03-1.57; p=0.02), and for bevacizumab-XELOX versus FOLFOX4 was 1.15 (0.93-1.42; p=0.21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3-5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab-XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab-FOLFOX4: 297 [26%]; bevacizumab-XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab-FOLFOX4, and five receiving bevacizumab-XELOX. Interpretation: Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer.

Effectiveness of a multifactorial falls prevention program in community-dwelling older people when compared to usual care: study protocol for a randomised controlled trial (Prevquedas Brazil)

Background Falling in older age is a major public health concern due to its costly and disabling consequences. However very few randomised controlled trials (RCTs) have been conducted in developing countries, in which population ageing is expected to be particularly substantial in coming years. This article describes the design of an RCT to evaluate the effectiveness of a multifactorial falls prevention program in reducing the rate of falls in community-dwelling older people. Methods/design Multicentre parallel-group RCT involving 612 community-dwelling men and women aged 60 years and over, who have fallen at least once in the previous year. Participants will be recruited in multiple settings in Sao Paulo, Brazil and will be randomly allocated to a control group or an intervention group. The usual care control group will undergo a fall risk factor assessment and be referred to their clinicians with the risk assessment report so that individual modifiable risk factors can be managed without any specific guidance. The intervention group will receive a 12-week Multifactorial Falls Prevention Program consisting of: an individualised medical management of modifiable risk factors, a group-based, supervised balance training exercise program plus an unsupervised home-based exercise program, an educational/behavioral intervention. Both groups will receive a leaflet containing general information about fall prevention strategies. Primary outcome measures will be the rate of falls and the proportion of fallers recorded by monthly falls diaries and telephone calls over a 12 month period. Secondary outcomes measures will include risk of falling, fall-related self-efficacy score, measures of balance, mobility and strength, fall-related health services use and independence with daily tasks. Data will be analysed using the intention-to-treat principle.The incidence of falls in the intervention and control groups will be calculated and compared using negative binomial regression analysis. Discussion This study is the first trial to be conducted in Brazil to evaluate the effectiveness of an intervention to prevent falls. If proven to reduce falls this study has the potential to benefit older adults and assist health care practitioners and policy makers to implement and promote effective falls prevention interventions. Trial registration ClinicalTrials.gov (NCT01698580)

Efficacy of graded activity versus supervised exercises in patients with chronic non-specific low back pain: protocol of a randomised controlled trial

Abstract Background Low back pain is a relevant public health problem, being an important cause of work absenteeism worldwide, as well as affecting the quality of life of sufferers and their individual functional performances. Supervised active physical routines and of cognitive-behavioral therapies are recommended for the treatment of chronic Low back pain, although evidence to support the effectiveness of different techniques is missing. Accordingly, the aim of this study is to contrast the effectiveness of two types of exercises, graded activity or supervised, in decreasing symptoms of chronic low back pain. Methods/design Sample will consist of 66 patients, blindly allocated into one of two groups: 1) Graded activity which, based on an operant approach, will use time-contingent methods aiming to increase participants’ activity levels; 2) Supervised exercise, where participants will be trained for strengthening, stretching, and motor control targeting different muscle groups. Interventions will last one hour, and will happen twice a week for 6 weeks. Outcomes (pain, disability, quality of life, global perceived effect, return to work, physical activity, physical capacity, and kinesiophobia) will be assessed at baseline, at treatment end, and three and six months after treatment end. Data collection will be conducted by an investigator blinded to treatment allocation. Discussion This project describes the randomisation method that will be used to compare the effectiveness of two different treatments for chronic low back pain: graded activity and supervised exercises. Since optimal approach for patients with chronic back pain have yet not been defined based on evidence, good quality studies on the subject are necessary. Trial registration NCT01719276