The impact of a self-development coaching programme on medical and dental students’ psychological health and academic performance: A randomised controlled trial

Background Psychological distress is well-documented worldwide among medical and dental students. Few studies have assessed the impact of self-development coaching programs on the students’ psychological health. The aim of the study was to evaluate the effect of a self-development coaching programme on the psychological health and academic performance of preclinical medical and dental students at Umm Al-Qura University, Saudi Arabia. Methods Four-hundred and twenty-two participants (n = 422, 20–22 years) fulfilled the study requirements and were invited into a parallel-randomised controlled trial that was partially blinded. Participants were stratified by faculty, gender, and academic year, and then randomised. A total of 156 students participated in the intervention group (IG) and 163 students participated in the control group (CG). The IG received the selfdevelopment programme, involving skills and strategies aimed to improve students’ psychological health and academic performance, through a two-day workshop. Meanwhile, the CG attended an active placebo programme focussing on theoretical information that was delivered through a five-hour workshop. Both programmes were conducted by the same presenter during Week 1 of the second semester of the 2012–2013 academic year. Data were gathered immediately before (T1), one week after (T2) and five weeks (T3) after the intervention. Psychological health was measured using the Depression Anxiety Stress Scale (DASS-21), the General Self-Efficacy (GSE), and the Satisfaction With Life Scale (SWLS). Academic performance was measured using students’ academic weighted grades (WG). Student cognitive and emotional perceptions of the intervention were measured using the Credibility/Expectancy Questionnaire (CEQ). Results Data from 317 students, who completed the follow ups, were analysed across the three time periods (IG, n = 155; CG, n = 162). The baseline variables and demographic data of the IG and CG were not significantly different. The IG showed short-term significant reductions in depression and anxiety in compared to CG from T1 to T2. The short-term changes in stress, GSE and SWLS of the IG were not significantly different from those of the CG. While both groups showed a significant change on most of the psychological variables from T1 to T3, no significant differences were found between the groups in this period. In addition, no significant difference was found in WG between the IG and CG after the intervention. No harms relevant to the intervention were reported. Conclusion The investigated self-development coaching programme showed only a short-term improvement on depression and anxiety compared with an active control. There was no effect of the intervention on academic performance.

Fall rates in hospital rehabilitation units after individualised patient and staff education programmes: A pragmatic, stepped-wedge, cluster-randomised controlled trial

- Background Falls are the most frequent adverse events that are reported in hospitals. We examined the effectiveness of individualised falls-prevention education for patients, supported by training and feedback for staff, delivered as a ward-level programme. - Methods Eight rehabilitation units in general hospitals in Australia participated in this stepped-wedge, cluster-randomised study, undertaken during a 50 week period. Units were randomly assigned to intervention or control groups by use of computer-generated, random allocation sequences. We included patients admitted to the unit during the study with a Mini-Mental State Examination (MMSE) score of more than 23/30 to receive individualised education that was based on principles of changes in health behaviour from a trained health professional, in addition to usual care. We provided information about patients' goals, feedback about the ward environment, and perceived barriers to engagement in falls-prevention strategies to staff who were trained to support the uptake of strategies by patients. The coprimary outcome measures were patient rate of falls per 1000 patient-days and the proportion of patients who were fallers. All analyses were by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials registry, number ACTRN12612000877886). - Findings Between Jan 13, and Dec 27, 2013, 3606 patients were admitted to the eight units (n=1983 control period; n=1623 intervention period). There were fewer falls (n=196, 7·80/1000 patient-days vs n=380, 13·78/1000 patient-days, adjusted rate ratio 0·60 [robust 95% CI 0·42–0·94], p=0·003), injurious falls (n=66, 2·63/1000 patient-days vs 131, 4·75/1000 patient-days, 0·65 [robust 95% CI 0·42–0·88], p=0·006), and fallers (n=136 [8·38%] vs n=248 [12·51%] adjusted odds ratio 0·55 [robust 95% CI 0·38 to 0·81], p=0·003) in the intervention compared with the control group. There was no significant difference in length of stay (intervention median 11 days [IQR 7–19], control 10 days [6–18]). - Interpretation Individualised patient education programmes combined with training and feedback to staff added to usual care reduces the rates of falls and injurious falls in older patients in rehabilitation hospital-units.

Effect of an interactive therapeutic robotic animal on engagement, mood states, agitation and psychotropic drug use in people with dementia: A cluster-randomised controlled trial protocol

Introduction: Apathy, agitated behaviours, loneliness and depression are common consequences of dementia. This trial aims to evaluate the effect of a robotic animal on behavioural and psychological symptoms of dementia in people with dementia living in long-term aged care. Methods and analysis: A cluster-randomised controlled trial with three treatment groups: PARO (robotic animal), Plush-Toy (non-robotic PARO) or Usual Care (Control). The nursing home sites are Australian Government approved and accredited facilities of 60 or more beds. The sites are located in South-East Queensland, Australia. A sample of 380 adults with a diagnosis of dementia, aged 60 years or older living in one of the participating facilities will be recruited. The intervention consists of three individual 15 min non-facilitated sessions with PARO or Plush- Toy per week, for a period of 10 weeks. The primary outcomes of interest are improvement in agitation, mood states and engagement. Secondary outcomes include sleep duration, step count, change in psychotropic medication use, change in treatment costs, and staff and family perceptions of PARO or Plush-Toy. Video data will be analysed using Noldus XT Pocket Observer; descriptive statistics will be used for participants’ demographics and outcome measures; cluster and individual level analyses to test all hypotheses and Generalised Linear Models for cluster level and Generalised Estimation Equations and/or Multi-level Modeling for individual level data. Ethics and dissemination: The study participants or their proxy will provide written informed consent. The Griffith University Human Research Ethics Committee has approved the study (NRS/03/14/HREC). The results of the study will provide evidence of the efficacy of a robotic animal as a psychosocial treatment for the behavioural and psychological symptoms of dementia. Findings will be presented at local and international conference meetings and published in peer-reviewed journals.

The cost-effectiveness of the MobileMums intervention to increase physical activity among mothers with young children: A Markov model informed by a randomised controlled trial

Objectives: To determine the cost-effectiveness of the MobileMums intervention. MobileMums is a 12-week programme which assists mothers with young children to be more physically active, primarily through the use of personalised SMS text-messages. Design: A cost-effectiveness analysis using a Markov model to estimate and compare the costs and consequences of MobileMums and usual care. Setting: This study considers the cost-effectiveness of MobileMums in Queensland, Australia. Participants: A hypothetical cohort of over 36 000 women with a child under 1 year old is considered. These women are expected to be eligible and willing to participate in the intervention in Queensland, Australia. Data sources: The model was informed by the effectiveness results from a 9-month two-arm community-based randomised controlled trial undertaken in 2011 and registered retrospectively with the Australian Clinical Trials Registry (ACTRN12611000481976). Baseline characteristics for the model cohort, treatment effects and resource utilisation were all informed by this trial. Main outcome measures: The incremental cost per quality-adjusted life year (QALY) of MobileMums compared with usual care. Results: The intervention is estimated to lead to an increase of 131 QALYs for an additional cost to the health system of 1.1 million Australian dollars (AUD). The expected incremental cost-effectiveness ratio for MobileMums is 8608 AUD per QALY gained. MobileMums has a 98% probability of being cost-effective at a cost-effectiveness threshold of 64 000 AUD. Varying modelling assumptions has little effect on this result. Conclusions: At a cost-effectiveness threshold of 64 000 AUD, MobileMums would likely be a cost-effective use of healthcare resources in Queensland, Australia. Trial registration number: Australian Clinical Trials Registry; ACTRN12611000481976.

Finding My Way: Protocol of a randomised controlled trial evaluating an internet self-help program for cancer-related distress

Background A cancer diagnosis elicits greater distress than any other medical diagnosis, and yet very few studies have evaluated the efficacy of structured online self-help therapeutic programs to alleviate this distress. This study aims to assess the efficacy over time of an internet Cognitive Behaviour Therapy (iCBT) intervention (‘Finding My Way’) in improving distress, coping and quality of life for individuals with a recent diagnosis of early stage cancer of any type. Methods/Design The study is a multi-site Randomised Controlled Trial (RCT) seeking to enrol 188 participants who will be randomised to either the Finding My Way Intervention or an attention-control condition. Both conditions are delivered online; with 6 modules released once per week, and an additional booster module released one month after program-completion. Participants complete online questionnaires on 4 occasions: at baseline (immediately prior to accessing the modules); post-treatment (immediately after program-completion); then three and six months later. Primary outcomes are general distress and cancer-specific distress, with secondary outcomes including Health-Related Quality of Life (HRQoL), coping, health service utilisation, intervention adherence, and user satisfaction. A range of baseline measures will be assessed as potential moderators of outcomes. Eligible participants are individuals recently diagnosed with any type of cancer, being treated with curative intent, aged over 18 years with sufficient English language literacy, internet access and an active email account and phone number. Participants are blinded to treatment group allocation. Randomisation is computer generated and stratified by gender. Discussion Compared to the few prior published studies, Finding My Way will be the first adequately powered trial to offer an iCBT intervention to curatively treated patients of heterogeneous cancer types in the immediate post-diagnosis/treatment period. If found efficacious, Finding My Way will assist with overcoming common barriers to face-to-face therapy in a cost-effective and accessible way, thus helping to reduce distress after cancer diagnosis and consequently decrease the cancer burden for individuals and the health system. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613000001​796 16.10.13

Randomised controlled trial of three burns dressings for partial thickness burns in children

BACKGROUND This study compared the effects of three silver dressing combinations on small to medium size acute partial thickness burns in children, focusing on re-epithelialization time, pain and distress during dressing changes. METHOD Children (0-15 years) with clean, ≤ 10% total body surface area (TBSA) partial thickness burns who met the inclusion criteria were included in the study. Children received either (1) Acticoat™; (2) Acticoat™ with Mepitel™; or (3) Mepilex Ag™ dressings. Measures of burn re-epithelialization, pain, and distress were recorded at dressing changes every 3-5 days until full re-epithelialization occurred. RESULTS One hundred and three children were recruited with 96 children included for analysis. No infections were detected for the course of the study. When adjusted for burn depth, Acticoat™ significantly increased the expected days to full re-epithelialization by 40% (IRR = 1.40; 95% CI: 1.14-1.73, p < 0.01) and Acticoat™ with Mepitel™ significantly increased the expected days to full re-epithelialization by 33% (IRR = 1.33; 95% CI: 1.08-1.63, p ≤ 0.01) when compared to Mepilex Ag™. Expected FLACC scores in the Mepilex Ag™ group were 32% lower at dressing removal (p = 0.01) and 37% lower at new dressing application (p = 0.04); and scores in the Acticoat™ with Mepitel™ group were 23% lower at dressing removal (p = 0.04) and 40% lower at new dressing application (p < 0.01), in comparison to the Acticoat™ group. Expected Visual Analog Scale-Pain (VAS-P) scores were 25% lower in the Mepilex Ag™ group at dressing removal (p = 0.04) and 34% lower in the Acticoat™ with Mepitel™ group (p = 0.02) at new dressing application in comparison to the Acticoat™ group. There was no significant difference between the Mepilex Ag™ and the Acticoat™ with Mepitel™ groups at all timepoints and with any pain measure. CONCLUSION Mepilex Ag™ is an effective silver dressing, in terms of accelerated wound re-epithelialization time (compared to Acticoat™ and Acticoat™ with Mepitel™) and decreased pain during dressing changes (compared to Acticoat™), for clean, < 10% TBSA partial thickness burns in children.

The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: A randomised controlled trial

BACKGROUND Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.

A multi-centre open-label randomised non-inferiority trial comparing watchful waiting to antibiotic treatment for acute otitis media without perforation in low-risk urban Aboriginal and Torres Strait Islander children (the WATCH trial): study protocol for a randomised controlled trial

Background Treatment guidelines recommend watchful waiting for children older than 2 years with acute otitis media (AOM) without perforation, unless they are at high risk of complications. The high prevalence of chronic suppurative otitis media (CSOM) in remote Aboriginal and Torres Strait Islander communities leads these children to be classified as high risk. Urban Aboriginal and Torres Strait Islander children are at lower risk of complications, but evidence to support the subsequent recommendation for watchful waiting in this population is lacking. Methods/Design This non-inferiority multi-centre randomised controlled trial will determine whether watchful waiting is non-inferior to immediate antibiotics for urban Aboriginal and Torres Strait Islander children with AOM without perforation. Children aged 2 − 16 years with AOM who are considered at low risk for complications will be recruited from six participating urban primary health care services across Australia. We will obtain informed consent from each participant or their guardian. The primary outcome is clinical resolution on day 7 (no pain, no fever of at least 38 °C, no bulging eardrum and no complications of AOM such as perforation or mastoiditis) as assessed by general practitioners or nurse practitioners. Participants and outcome assessors will not be blinded to treatment. With a sample size of 198 children in each arm, we have 80 % power to detect a non-inferiority margin of up to 10 % at a significance level of 5 %, assuming clinical improvement of at least 80 % in both groups. Allowing for a 20 % dropout rate, we aim to recruit 495 children. We will analyse both by intention-to-treat and per protocol. We will assess the cost- effectiveness of watchful waiting compared to immediate antibiotic prescription. We will also report on the implementation of the trial from the perspectives of parents/carers, health professionals and researchers. Discussion The trial will provide evidence for the safety and effectiveness of watchful waiting for the management of AOM in Aboriginal and Torres Strait Islander children living in urban settings who are considered to be at low risk of complications.

Women’s Wellness after Cancer Program Study (WWACP)– A multi centre randomised controlled trial examining the benefits and cost effectiveness of an Evidenced Based, e-health intervention

Background Advances in cancer diagnosis and treatment have significantly improved survival rates, through their subsequent health needs are often not adequately addressed by current health services. National Health and Medical Research Council (NHMRC) Partnerships Project awarded a national collaborative project to develop, trial and evaluate clinical benefits and cost effectiveness of an e-health enabled structured health promotion intervention - The Women’s Wellness after Cancer Program (WWACP). The aim of this e-health enabled multimodal intervention is to improve health related quality of life in women previously treated for target cancers. Aim The WWACP is a 12-week web based, interactive, holistic program. Primary outcomes for this project are to promote a positive change in health-related quality of life (HRQoL) and reduction in Body Mass Index (BMI) in the women undertaking WWACP compared to women who receive usual care. Secondary outcomes include managing other side effects of cancer treatment through evidence-based nutrition and exercise practices, dealing with stress, sleep, menopause and sexuality issues. Methods The single-blinded multi-center randomized controlled trial recruited a toatl of 330 women within 24 months of completion of chemotherapy and /or radiotherapy. Women were randomly assigned to either a usual care or intervention group. Women provided with the intervention were provided with an interactive iBook and journal, web interface, and three virtual consultations by experienced cancer nurses. A variety of methods were utilized, to enable positive self- efficacy and lifestyle changes. These include online coaching with a registered nurse trained in the intervention, plus written educational and health promotional information. The program has been delivered through the e-health enabled interfaces, which enables virtual delivery via desktop and mobile computing devices. Importantly this enables accessibility for rural and regional women in Australia who are frequently geographically disadvantaged in terms of health care provision. Results Research focusing on alternative methods of delivering post treatment / or survivorship care in cancer utilizing web based interfaces is limited, but emerging evidence suggests that Internet interventions can increase psychological and physical wellbeing in cancer patients. The WWACP trial aims to establish the effectiveness of delivery of the program in terms of positive patient outcomes and cost effective, flexibility. The trial will be completed in September and results will be presented at the conference. Conclusions Women after acute hematological, breast and gynecological cancer treatments demonstrate good cancer survival rates and face residual health problems which are amenable to behavioral interventions. The conclusion of active treatment is a key 'teachable moment' in which sustainable positive lifestyle change can be achieved if patients receive education and psychological support which targets key treatment related health problems and known chronic disease risk factors.

IMPOSE (IMProving Outcomes after Sepsis)—the effect of a multidisciplinary follow-up service on health-related quality of life in patients postsepsis syndromes—a double-blinded randomised controlled trial: protocol

Introduction Patients post sepsis syndromes have a poor quality of life and a high rate of recurring illness or mortality. Follow-up clinics have been instituted for patients postgeneral intensive care but evidence is sparse, and there has been no clinic specifically for survivors of sepsis. The aim of this trial is to investigate if targeted screening and appropriate intervention to these patients can result in an improved quality of life (Short Form 36 health survey (SF36V.2)), decreased mortality in the first 12 months, decreased readmission to hospital and/or decreased use of health resources. Methods and analysis 204 patients postsepsis syndromes will be randomised to one of the two groups. The intervention group will attend an outpatient clinic two monthly for 6 months and receive screening and targeted intervention. The usual care group will remain under the care of their physician. To analyse the results, a baseline comparison will be carried out between each group. Generalised estimating equations will compare the SF36 domain scores between groups and across time points. Mortality will be compared between groups using a Cox proportional hazards (time until death) analysis. Time to first readmission will be compared between groups by a survival analysis. Healthcare costs will be compared between groups using a generalised linear model. Economic (health resource) evaluation will be a within-trial incremental cost utility analysis with a societal perspective. Ethics and dissemination Ethical approval has been granted by the Royal Brisbane and Women’s Hospital Human Research Ethics Committee (HREC; HREC/13/QRBW/17), The University of Queensland HREC (2013000543), Griffith University (RHS/08/14/HREC) and the Australian Government Department of Health (26/2013). The results of this study will be submitted to peer-reviewed intensive care journals and presented at national and international intensive care and/or rehabilitation conferences.

Evaluating the effectiveness of a self-management exercise intervention on wound healing, functional ability and health-related quality of life outcomes in adults with venous leg ulcers: a randomised controlled trial

Exercise that targets ankle joint mobility may lead to improvement in calf muscle pump function and subsequent healing. The objectives of this research were to assess the impact of an exercise intervention in addition to routine evidence-based care on the healing rates, functional ability and health-related quality of life for adults with venous leg ulcers (VLUs). This study included 63 patients with VLUs. Patients were randomised to receive either a 12-week exercise intervention with a telephone coaching component or usual care plus telephone calls at the same timepoints. The primary outcome evaluated the effectiveness of the intervention in relation to wound healing. The secondary outcomes evaluated physical activity, functional ability and health-related quality of life measures between groups at the end of the 12 weeks. A per protocol analysis complemented the effectiveness (intention-to-treat) analysis to highlight the importance of adherence to an exercise intervention. Intention-to-treat analyses for the primary outcome showed 77% of those in the intervention group healed by 12 weeks compared to 53% of those in the usual care group. Although this difference was not statistically significant due to a smaller than expected sample size, a 24% difference in healing rates could be considered clinically significant. The per protocol analysis for wound healing, however, showed that those in the intervention group who adhered to the exercise protocol 75% or more of the time were significantly more likely to heal and showed higher rates for wound healing than the control group (P = 0·01), that is, 95% of those who adhered in the intervention group healed in 12 weeks. The secondary outcomes of physical activity, functional ability and health-related quality of life were not significantly altered by the intervention. Among the secondary outcomes (physical activity, functional ability and health-related quality of life), intention-to-treat analyses did not support the effectiveness of the intervention. However, per protocol analyses revealed encouraging results with those participants who adhered more than 75% of the time (n = 19) showing significantly improved Range of Ankle Motion from the self-management exercise programme (P = 0·045). This study has shown that those participants who adhere to the exercise programme as an adjunctive treatment to standard care are more likely to heal and have better functional outcomes than those who do not adhere to the exercises in conjunction with usual care.

General Practitioner Antimicrobial Stewardship Programme Study (GAPS): protocol for a cluster randomised controlled trial

Background There is a strong link between antibiotic consumption and the rate of antibiotic resistance. In Australia, the vast majority of antibiotics are prescribed by general practitioners, and the most common indication is for acute respiratory infections. The aim of this study is to assess if implementing a package of integrated, multifaceted interventions reduces antibiotic prescribing for acute respiratory infections in general practice. Methods/design This is a cluster randomised trial comparing two parallel groups of general practitioners in 28 urban general practices in Queensland, Australia: 14 intervention and 14 control practices. The protocol was peer-reviewed by content experts who were nominated by the funding organization. This study evaluates an integrated, multifaceted evidence-based package of interventions implemented over a six month period. The included interventions, which have previously been demonstrated to be effective at reducing antibiotic prescribing for acute respiratory infections, are: delayed prescribing; patient decision aids; communication training; commitment to a practice prescribing policy for antibiotics; patient information leaflet; and near patient testing with C-reactive protein. In addition, two sub-studies are nested in the main study: (1) point prevalence estimation carriage of bacterial upper respiratory pathogens in practice staff and asymptomatic patients; (2) feasibility of direct measures of antibiotic resistance by nose/throat swabbing. The main outcome data are from Australia’s national health insurance scheme, Medicare, which will be accessed after the completion of the intervention phase. They include the number of antibiotic prescriptions and the number of patient visits per general practitioner for periods before and during the intervention. The incidence of antibiotic prescriptions will be modelled using the numbers of patients as the denominator and seasonal and other factors as explanatory variables. Results will compare the change in prescription rates before and during the intervention in the two groups of practices. Semi-structured interviews will be conducted with the general practitioners and practice staff (practice nurse and/or practice manager) from the intervention practices on conclusion of the intervention phase to assess the feasibility and uptake of the interventions. An economic evaluation will be conducted to estimate the costs of implementing the package, and its cost-effectiveness in terms of cost per unit reduction in prescribing. Discussion The results on the effectiveness, cost-effectiveness, acceptability and feasibility of this package of interventions will inform the policy for any national implementation.

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months [95% CI 10·6–12·9] with afatinib vs 10·9 months [9·1–11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57–0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9–15·0] with afatinib vs 11·5 months [10·1–13·1] with gefitinib; HR 0·73 [95% CI 0·58–0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.