Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes.

Defining the Therapeutic Range for Adalimumab and Predicting Response in Psoriasis: A Multicenter Prospective Observational Cohort Study.

Biologics have transformed management of inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by circulating drug levels has been proposed. We aimed to determine the real-world clinical utility of therapeutic drug monitoring in psoriasis. Within a multicenter (n = 60) prospective observational cohort, 544 psoriasis patients were included who were receiving adalimumab monotherapy and had at least one serum sample and Psoriasis Area and Severity Index (PASI) score available within the first year. We present models giving individualized probabilities of response for any given drug level: a minimally effective drug level of 3.2 µg/ml discriminates responders (PASI75 indicates 75% improvement in baseline PASI) from nonresponders, and gives an estimated PASI75 probability of 65% (95% confidence interval = 60-71). At 7 µg/ml, PASI75 probability is 81% (95% CI = 76-86); beyond 7 µg/ml, the drug level/response curve plateaus. Crucially, drug levels are predictive of response 6 months later, whether sampled early or at steady state. We confirm serum drug level to be the most important factor determining treatment response, highlighting the need to take drug levels into account when searching for biomarkers of response. This real-world study with pragmatic drug level sampling provides evidence to support the proactive measurement of adalimumab levels in psoriasis to direct treatment strategy, and is relevant to other inflammatory diseases.

Association of Serum Ustekinumab Levels With Clinical Response in Psoriasis.

IMPORTANCE: High-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab. OBJECTIVE: To evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria. EXPOSURE: Serum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES: Disease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline [primary outcome]), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less. RESULTS: A total of 491 patients (171 women and 320 men; mean [SD] age, 45.7 [12.8] years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of ≤1.5). CONCLUSIONS AND RELEVANCE: This real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.

Randomised trial of cord clamping and initial stabilisation at very preterm birth.

OBJECTIVES: For very preterm births, to compare alternative policies for umbilical cord clamping and immediate neonatal care. DESIGN: Parallel group randomised (1:1) trial, using sealed opaque numbered envelopes. SETTING: Eight UK tertiary maternity units. PARTICIPANTS: 261 women expected to have a live birth before 32 weeks, and their 276 babies. INTERVENTIONS: Cord clamping after at least 2 min and immediate neonatal care with cord intact, or clamping within 20 s and immediate neonatal care after clamping. MAIN OUTCOME MEASURES: Intraventricular haemorrhage (IVH), death before discharge. RESULTS: 132 women (137 babies) were allocated clamping ≥2 min and neonatal care cord intact, and 129 (139) clamping ≤20 s and neonatal care after clamping; six mother-infant dyads were excluded (2, 4) as birth was after 35+6 weeks, one withdrew (death data only available) (0, 1). Median gestation was 28.9 weeks for those allocated clamping ≥2 min, and 29.2 for those allocated clamping ≤20 s. Median time to clamping was 120 and 11 s, respectively. 7 of 135 infants (5.2%) allocated clamping ≥2 min died and 15 of 135 (11.1%) allocated clamping ≤20 s; risk difference (RD) -5.9% (95% CI -12.4% to 0.6%). Of live births, 43 of 134 (32%) had IVH vs 47 of 132 (36%), respectively; RD -3.5% (-14.9% to 7.8%). There were no clear differences in other outcomes for infants or mothers. CONCLUSIONS: This is promising evidence that clamping after at least 2 min and immediate neonatal care with cord intact at very preterm birth may improve outcome; a large trial is urgently needed. TRIAL REGISTRATION: ISRCTN 21456601.

Clinicians' views and experiences of offering two alternative consent pathways for participation in a preterm intrapartum trial: a qualitative study.

BACKGROUND: The Cord Pilot Trial compared alternative policies for timing of cord clamping at very preterm birth at eight UK hospitals. Preterm birth can be rapid and unexpected, allowing little time for the usual consent process. Therefore, in addition to the usual procedure for written consent, a two-stage pathway for consent for use when birth was imminent was developed. The aims of this study were to explore clinicians' views and experiences of offering two consent pathways for recruitment to a randomised trial of timing of cord clamping at very preterm birth. METHODS: This was a qualitative study using semi-structured interviews. Clinicians from eight hospitals in the UK who had been involved in offering consent to the Cord Pilot Trial were invited to take part in an interview. Clinicians were interviewed in person or by telephone. Interviews were analysed using inductive systematic thematic analysis. RESULTS: Seventeen clinicians who had either offered usual written consent only (n = 6) or both the two-stage pathway (with oral assent before the birth and written consent after the birth) and usual written consent (n = 11) were interviewed. Six themes were identified: (1) team approach to offering participation; (2) consent form as a record; (3) consent and participation as a continual process; (4) different consent pathways for different trials; (5) balance between time, information, and understanding; and (6) validity of consent. Overall, clinicians were supportive of the two-stage consent pathway. Some clinicians felt that in time-critical situations oral assent presented an advantage over the usual written consent as they provided information on a "need to know" basis. However, there was some concern about how much information should be given for oral assent, and how this is understood by women when birth is imminent. CONCLUSIONS: The two-stage pathway for consent developed for use in the Cord Pilot Trial when birth was imminent was acceptable to clinicians for comparable low-risk studies, although some concerns were raised about the practicalities of obtaining oral assent. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN21456601 . Registered on 28 February 2013.

Women's views and experiences of two alternative consent pathways for participation in a preterm intrapartum trial: a qualitative study.

BACKGROUND: The Cord Pilot Trial compared alternative policies for timing of cord clamping at very preterm birth at eight UK hospitals. In addition to standard written consent, an oral assent pathway was developed for use when birth was imminent. The aim of this study was to explore women's views and experiences of two alternative consent pathways to participate in the Cord Pilot Trial. METHODS: We conducted a qualitative study using semi-structured interviews. A total of 179 participants in the Cord Pilot Trial were sent a postal invitation to take part in interviews. Women who agreed were interviewed in person or by telephone to explore their experiences of two consent pathways for a preterm intrapartum trial. Data were analysed using inductive systematic thematic analysis. RESULTS: Twenty-three women who gave either written consent (n = 18) or oral assent followed by written consent (n = 5) to participate in the trial were interviewed. Five themes were identified: (1) understanding of the implications of randomisation, (2) importance of staff offering participation, (3) information about the trial and time to consider participation, (4) trial secondary in women's minds and (5) reasons for agreeing to take part in the trial. Experiences were similar for the two consent pathways. Women recruited by the oral assent pathway reported being given less information about the trial but felt it was sufficient to make a decision regarding participation. There were gaps in women's understanding of the trial and intervention, regardless of the consent pathway. CONCLUSIONS: Overall, women were positive about their experiences of being invited to participate in the trial. The oral assent pathway seems an acceptable option for women if the intervention is low-risk and time is limited. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN21456601 . Registered on 28 February 2013.

Cord pilot trial: update to randomised trial protocol.

BACKGROUND: The Cord Pilot Trial aimed to assess the feasibility of conducting a large UK randomised trial to compare the effects of alternative polices for timing of cord clamping (immediate within 20 seconds or deferred after at least 2 minutes) for very preterm birth before 32 weeks gestation. Initial recruitment was from March 2013 to February 2014, phase 2 was from March 2014 to February 2015. This paper updates the pilot trial protocol (Trials 15(1):258, 2014) and presents the changes for phase 2. METHODS: An electronic randomisation system was introduced at three of the eight pilot sites. For follow-up of children, the Parent Report of Children's Abilities--Revised (PARCA-R) will not be used. For children recruited to the trial during phase 2, follow-up at age 2 years (corrected for gestation at birth) will be by parent completed Ages and Stages Questionnaire (Squire J, Ages and Stages Questionnaires (ASQ), 2009) alone unless funds can be secured for the additional Bayley Scales of Infant Development III (Bayley N, Bayley Scales of Infant and Toddler Development, Third Edition. (Bayley-III), 2005) assessments. To assess accuracy of the cranial ultrasound diagnosis of intraventricular haemorrhage: (i) quality of the scans will be assessed using the British Society of Paediatric Radiology recommendations, and (ii) scan results will be confirmed by independent adjudication. Within and between adjudicator reliability will be assessed. In addition to the analyses planned to assess feasibility of the full trial based on data from the first year of recruitment, data on compliance and outcomes will be presented by allocated group for all women and babies recruited. TRIAL REGISTRATION: ISRCTN21456601, registered on 28 February 2013.

Cord pilot trial - immediate versus deferred cord clamping for very preterm birth (before 32 weeks gestation): study protocol for a randomized controlled trial.

BACKGROUND: Preterm birth is the most important single determinant of adverse outcome in the United Kingdom; one in every 70 babies (1.4%) is born before 32 weeks (very preterm), yet these births account for over half of infant deaths.Deferring cord clamping allows blood flow between baby and placenta to continue for a short time. This often leads to increased neonatal blood volume at birth and may allow longer for transition to the neonatal circulation. Optimal timing for clamping the cord remains uncertain, however. The Cochrane Review suggests that deferring umbilical cord clamping for preterm births may improve outcome, but larger studies reporting substantive outcomes and with long-term follow-up are needed. Studies of the physiology of placental transfusion suggest that flow in the umbilical cord at very preterm birth may continue for several minutes. This pilot trial aims to assess the feasibility of conducting a large randomised trial comparing immediate and deferred cord clamping in the UK. METHODS/DESIGN: Women are eligible for the trial if they are expected to have a live birth before 32 weeks gestation. Exclusion criteria are known monochorionic twins or clinical evidence of twin-twin transfusion syndrome, triplet or higher order multiple pregnancy, and known major congenital malformation. The interventions will be cord clamping within 20 seconds compared with cord clamping after at least two minutes. For births with cord clamping after at least two minutes, initial neonatal care is at the bedside. For the pilot trial, outcomes include measures of recruitment, compliance with the intervention, retention of participants and data quality for the clinical outcomes.Information about the trial is available to women during their antenatal care. Women considered likely to have a very preterm birth are approached for informed consent. Randomisation is close to the time of birth. Follow-up for the women is for one year, and for the children to two years of age (corrected for gestation at birth). The target sample size is 100 to 110 mother-infant pairs recruited over 12 months at eight sites. TRIAL REGISTRATION: ISRCTN21456601, registered on 28 February 2013.

Implementing the NICE osteoarthritis guidelines: a mixed methods study and cluster randomised trial of a model osteoarthritis consultation in primary care--the Management of OsteoArthritis In Consultations (MOSAICS) study protocol.

BACKGROUND: There is as yet no evidence on the feasibility of implementing recommendations from the National Institute of Health and Care Excellence (NICE) osteoarthritis (OA) guidelines in primary care, or of the effect these recommendations have on the condition. The primary aim of this study is to determine the clinical and cost effectiveness of a model OA consultation (MOAC), implementing the core recommendations from the NICE OA guidelines in primary care. Secondary aims are to investigate the impact, feasibility and acceptability of the MOAC intervention; to develop and evaluate a training package for management of OA by general practitioners (GPs) and practice nurses; test the feasibility of deriving 'quality markers' of OA management using a new consultation template and medical record review; and describe the uptake of core NICE OA recommendations in participants aged 45 years and over with joint pain. DESIGN: A mixed methods study with a nested cluster randomised controlled trial. METHOD: This study was developed according to a defined theoretical framework (the Whole System Informing Self-management Engagement). An overarching model (the Normalisation Process Theory) will be employed to undertake a comprehensive 'whole-system' evaluation of the processes and outcomes of implementing the MOAC intervention. The primary outcome is general physical health (Short Form-12 Physical component score [PCS]) (Ware 1996). The impact, acceptability and feasibility of the MOAC intervention at practice level will be assessed by comparing intervention and control practices using a Quality Indicators template and medical record review. Impact and acceptability of the intervention for patients will be assessed via self-completed outcome measures and semi-structured interviews. The impact, acceptability and feasibility of the MOAC intervention and training for GPs and practice nurses will be evaluated using a variety of methods including questionnaires, semi-structured interviews, and observations. DISCUSSION: The main output from the study will be to determine whether the MOAC intervention is clinically and cost effective. Additional outputs will be the development of the MOAC for patients consulting with joint pain in primary care, training and educational materials, and resources for patients and professionals regarding supported self-management and uptake of NICE guidance. TRIAL REGISTRATION: ISRCTN number: ISRCTN06984617.