Objective: Adaptive designs can enable highly sophisticated and efficient early phase trials, but the clinical inference from these trials is surrounded by complexity, and currently there is a paucity but steadily increasing amount of use of these designs in all fields of medicine. We aim to review early phase trials in RA to discover those that have used adaptive designs and benchmark trial characteristics.

Methods: From an OVID search for journal articles reporting the results of early phase trials in rheumatology, 35 studies were found, with 9 subsequently excluded; 11 were added from manual searches and 19 from searching the references. Study characteristics were extracted from the 56 papers (describing 62 trials), including the number of arms, number of patients, the primary outcome and when it was measured.

Result: One early phase trial using an adaptive design was found. The benchmark early phase trial in RA is a phase II double-blinded randomized trial, with four arms (one control and three intervention), each with 34 patients, and ACR20 measured at 16 weeks as the primary outcome.

Conclusion: The one adaptive design reviewed here, and a simulation study found in the search, both indicate that adaptive designs can be applied to early phase trials in RA. We have described the benchmark, which the efficiency of early phase trials using an adaptive design needs to exceed. These efficient designs could drive down numbers required, time for data collection and thus cost. Changes have been suggested, but more needs to be done.

OBJECTIVES: We compared the effectiveness of an intensive smoking cessation intervention among smokers with and without a severe mental disorder (SMD) and identified factors associated with successful quitting. The main hypothesis was that smokers with an SMD would be less likely to stay continuously smoke-free for 6 months.

DESIGN: A prospective cohort study.

SETTING: In all, 302 smoking cessation clinics in Denmark from municipal clinics, pharmacies, hospitals, midwives, primary care facilities and other private providers who reported data to the national Danish Smoking Cessation Database from 2006 to 2016 participated in this study.

PARTICIPANTS: A total of 38 293 patients from the Danish Smoking Cessation Database. Patients with an SMD were identified by linking data to the Danish National Patient Register. Diagnoses of organic mental disorders (F0 chapter) or intellectual disabilities (F7 chapter) were not included. Smokers ≥18 years old who were attending a Gold Standard Programme (GSP) with planned follow-up were included. Smokers not wanting contact after 6 months were excluded.

INTERVENTIONS: A comprehensive manual-based smoking cessation intervention comprising five meetings over a 6-week period (the GSP).

MAIN OUTCOME MEASURES: Self-reported continuous abstinence at the 6-month follow-up.

RESULTS: In all, 69% of the participants participated in the follow-up after 6 months. The overall rate of successful quitting was high but significantly lower in SMD smokers (29% vs 38%; OR 0.74; 95% CI 0.68 to 0.80). Variables associated with successful quitting were compliance (defined as attending ≥75% of the planned meetings), older age and male gender as well as not being disadvantaged, heavy smoking or recommendation of intervention by health professionals.

CONCLUSIONS: Only 29% of smokers with an SMD successfully quit smoking which was significantly lower than the 38% of smokers without an SMD. Compliance was the most important predictor for successful quitting.

INTRODUCTION: An unbalanced intestinal microbiota may mediate activation of the inflammatory pathways seen in psoriatic arthritis (PsA). A randomised, placebo-controlled trial of faecal microbiota transplantation (FMT) infused into the small intestine of patients with PsA with active peripheral disease who are non-responsive to methotrexate (MTX) treatment will be conducted. The objective is to explore clinical aspects associated with FMT performed in patients with PsA.

METHODS AND ANALYSIS: This trial is a randomised, two-centre stratified, double-blind (patient, care provider and outcome assessor), placebo-controlled, parallel-group study. Eighty patients will be included and randomised (1:1) to either placebo (saline) or FMT provided from an anonymous healthy donor. Throughout the study, both groups will continue the weekly self-administered subcutaneous MTX treatment, remaining on the preinclusion dosage (15-25 mg/week). The clinical measures of psoriasis and PsA disease activity used include the Short (2-page) Health Assessment Questionnaire, the Dermatology Quality of Life Index, the Spondyloarthritis Research Consortium of Canada Enthesitis Index, the Psoriasis Area Severity Index, a dactylitis digit count, a swollen/tender joint count (66/68), plasma C reactive protein as well as visual analogue scales for pain, fatigue and patient and physician global assessments. The primary end point is the proportion of patients who experience treatment failure during the 6-month trial period. The number of adverse events will be registered throughout the study.

ETHICS AND DISSEMINATION: This is a proof-of-concept clinical trial and will be performed in agreement with Good Clinical Practice standards. Approvals have been obtained from the local Ethics Committee (DK-S-20150080) and the Danish Data Protection Agency (15/41684). The study has commenced in May 2017. Dissemination will be through presentations at national and international conferences and through publications in international peer-reviewed journal(s).

TRIAL REGISTRATION NUMBER: NCT03058900; Pre-results.

BACKGROUND: Observational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one-second (FEV1) and forced vital capacity (FVC).

METHODS: We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI-associated single nucleotide polymorphisms (SNPs). Results were pooled in meta-analyses and expressed as odds ratios (ORs) or β-estimates with 95% confidence interval (CI).

RESULTS: The GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002) or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI-increasing allele. The GRS was significantly associated with decrease in FEV1: β=-0.0012 (95% CI: -0.0019, -0.0006) and FVC: β=-0.0022 (95% CI: -0.0031, -0.0014) per BMI-increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0-15 mL decrease) and a 16 ml decrease in FVC (95% CI: 7.0-24 mL decrease) per 1 kg/m(2) higher BMI.

CONCLUSIONS: The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.

INTRODUCTION: The number of persons living with a chronic condition is increasing worldwide. Conditions are considered chronic when lasting 1 year or more and requiring ongoing medical attention and/or limiting activities of daily living (ADL). Besides medical treatment, physical exercise to improve body functions is recommended and prescribed. However, improvements in body functions do not necessarily improve ability to perform ADL. Thus, it is necessary to develop interventions aiming directly at enhancing ADL ability. As a part of the research programme 'A Better Everyday Life', the first version of the ABLE intervention programme was developed.

METHODS AND ANALYSIS: This feasibility study examine the perceived value and acceptability of the ABLE programme by evaluating the fidelity, reach, dose and potential outcomes using a pretest and post-test design involving 30 persons living with chronic conditions. Qualitative interviews among occupational therapists delivering and participants receiving the ABLE programme will be conducted to explore aspects affecting the intervention.

ETHICS AND DISSEMINATION: The results will form the base for refinement of the ABLE programme and planning of a large-scale randomised controlled trial investigating the effect of the programme on self-reported and observed ADL ability. Dissemination will include peer-reviewed publications and presentations at national and international conferences.

PROTOCOL VERSION: 7 November 2017: v ersion 1.0. 19 February 2018: v ersion 2.0.

TRIAL REGISTRATION NUMBER: NCT03335709; Pre-results.

OBJECTIVE: To examine if fetal exposure to a small dosage of extra vitamin D from food fortification was associated with a decrease in the risk of pre-eclampsia later in life.

DESIGN: Cancellation of the mandatory vitamin D fortification of margarine in 1985 created a societal experiment, with entire adjacent birth cohorts exposed or unexposed to extra vitamin D during fetal development. The Danish national medical health registries allowed the identification of pre-eclampsia cases later in life among all exposed and unexposed female individuals.

SETTING: Denmark.

SUBJECTS: Women born between June 1983 and August 1988, who gave birth to their first child at age 14·5-27·5 years (n 32 621).

RESULTS: OR (95 % CI) for pre-eclampsia among women exposed v. unexposed to extra vitamin D from fortification during fetal development was 0·86 (0·76, 0·97). Exposure to extra vitamin D was associated with further reduced odds of pre-eclampsia (0·49 (0·34, 0·72)) among current smokers, but not among former smokers and non-smokers.

CONCLUSIONS: Additional vitamin D in fetal life from food fortification seems to reduce the risk of pre-eclampsia later in life. The risk reduction may be particularly strong among women who smoke during pregnancy.