The ASCEND study: protocol for a feasibility study to evaluate an early social communication intervention for young children with Down syndrome.

BACKGROUND: Down syndrome is the most common cause of learning disability, affecting approximately 1 in every 700 babies. Children with Down syndrome have particular difficulties with speech and language. This makes it challenging for them to participate fully in life, access healthcare services and educational opportunities. Improving the language skills of young children with Down syndrome is vital for their future social and emotional well-being and behaviour, and consequently contribution to society. As Down syndrome is detected before or at birth, we can provide support from early on. There are currently no standard interventions for improving the language skills of children with Down syndrome under the age of 36 months. Evidence suggests that early parent-based interventions may be effective in improving language outcomes. In partnership with parents and speech and language therapists, we have co-developed an intervention focusing on early social communication skills and our preliminary work shows that it can lead to better language in children with Down syndrome. Our aim is to carry out a feasibility study which will inform a future pilot/full trial to test whether the intervention is effective in improving language skills before children with Down syndrome start school. METHODS: This is a two-arm feasibility randomised controlled trial (RCT), with 1:1 randomisation stratified by trial site comparing the intervention (plus standard NHS speech and language therapy) with no intervention (standard NHS speech and language therapy only). We aim to recruit between 25 and 30 children with Down syndrome aged between 11 and 36 months. Sites are defined by the geographical boundaries of three National Health Service (NHS) Trusts. Recruitment is from NHS Speech and Language Therapist caseloads within the 3 Trusts, and self-referral. In the intervention arm, parents/guardians will receive brief training on the parent-based intervention and a manual to follow with their child for 10 weeks. The children's language and early communication skills and family health outcomes will be assessed by a blinded assessor at baseline, post-intervention and 6 month follow-up. Questionnaire and semi-structured interviews will explore the acceptability of the intervention to parents and SLTs. DISCUSSION: The feasibility study's outcomes will determine whether it would be viable to progress to a full-trial and whether adjustments need to made to the procedures, data collection methods, intervention delivery and the intensity of support needed. We want to assess whether our early intervention can be delivered and rolled out through NHS Speech and Language Therapy (SLT) Services. We anticipate that NHS SLT Services will need to make ongoing changes due to the COVID-19 pandemic, so it is likely that we will need to make adjustments for the definitive trial. We will also calculate descriptive statistics of the language outcome measure which we will use for any future sample size calculation. TRIAL REGISTRATION: ISRCTN13902755. Registered on 25 August 2020. http://www.isrctn.com/ISRCTN13902755.

Effects of a topical treatment with spleen tyrosine kinase inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: Results of a phase 1a/b randomised double-blind placebo-controlled study.

AIMS: To explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models. METHODS: Healthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients. RESULTS: Thirty-four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0-24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in 4 of 9 patients, who demonstrated either a complete inhibition of ColdU to ≤4°C (n = 2) or partial response (reduction by >4°C, n = 2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the defined area urticaria activity score PD endpoint. CONCLUSION: This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed. (NCT02424799).

Safety of Repeated Open-Label Treatment Courses of Intravenous Ofatumumab, a Human Anti-CD20 Monoclonal Antibody, in Rheumatoid Arthritis: Results from Three Clinical Trials.

OBJECTIVES: To investigate the safety of ofatumumab retreatment in rheumatoid arthritis. METHODS: Patients with active rheumatoid arthritis participating in two phase III trials (OFA110635 and OFA110634) and a phase II extension trial (OFA111752) received individualised open-label ofatumumab retreatment (700 mg X 2 intravenous infusions two weeks apart) ≥24 weeks following the first course and ≥16 weeks following further courses. Retreatment required evidence of clinical response followed by disease relapse. These studies were prematurely terminated by the sponsor to refocus development on subcutaneous delivery. Due to differences in study designs and populations, data are summarised separately for each study. RESULTS: 483 patients (243, 148 and 92 in OFA110635, OFA110634 and OFA111752 respectively) received up to 7 treatment courses of intravenous ofatumumab; cumulative duration of exposure was 463, 182 and 175 patient-years, respectively. Mean time between courses was 17-47 weeks. Ofatumumab induced a profound depletion of peripheral B-lymphocytes. Retreated patients derived benefit based on improvement in DAS28. Adverse events were reported for 93% (226/243), 91% (134/148) and 76% (70/92), serious adverse events for 18% (44/243), 20% (30/148) and 12% (11/92) and serious infections for 3% (8/243), 5% (7/148) and 1% (1/92) of patients in OFA110635, OFA110634 and OFA111752, respectively. The most common adverse events were infusion-related reactions during the first infusion of the first course (48-79%); serious infusion-related reactions were rare (<1% [1/243], 5% [8/148], and 1% [1/92] of patients). Two deaths occurred (fulminant hepatitis B virus infection and interstitial lung disease). CONCLUSIONS: Ofatumumab was generally well tolerated with no evidence of increased safety risks with multiple retreatments. Serious infections were uncommon and did not increase over time. TRIAL REGISTRATION: ClinicalTrials.gov 110635 ClinicalTrials.gov 110634 ClinicalTrials.gov 111752.

A model of skin inflammation in humans leads to a rapid and reproducible increase in the interferon response signature: a potential translational model for drug development.

OBJECTIVES: To investigate Toll-like receptor activation in human skin using tape stripping and imiquimod cream challenges in healthy volunteers. SUBJECTS, TREATMENT AND METHODS: Seventeen male Caucasian subjects underwent a baseline biopsy on their lower back prior to two tape stripping procedures 7 days apart. Subjects were then treated with 5% imiquimod for 2 and 4 days on separate sites in the same area. Further biopsies were taken 22-24 h after each challenge and mRNA and microRNA extracted and expression values analysed using robust statistical and pathway analysis methods. RESULTS: Fifteen of the 17 subjects completed the study according to protocol. No adverse events were associated with the procedures. A significant change (p < 0.05, fold change >1.5 or <-1.5) in mRNA expression of 7,996 genes was evident in biopsies taken at both time points post tape stripping, compared to baseline biopsy expression values. The induction of mRNAs involved in various pathways including adhesion and migration was evident. mRNA markers representing inflammatory cells [e.g., CD14, CD3E (p < 0.0001)] and mRNAs encoding genes regulated by type 1 interferon (IFN) [e.g., MX1, OAS1and CXCL10 (p < 0.0001)] were significantly up-regulated. IFNα and CXCL10 proteins were detectable in exudates released 1 and 4 h post tape stripping. A putative signalling network associating these transcripts and six microRNAs (hsa-miR, -31, -132, -155, 548c, 548n and 574) was identified using a meta-regulation network model. microRNAs not previously associated with IFN signalling have been identified. In contrast, only 223 known transcripts were significantly changed after imiquimod treatment, including CXCL10, and OAS1. CONCLUSION: Results suggest that IFN signalling is important in these translational models and novel miRNA may be new targets in the treatment of IFN associated skin disease.

Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis.

OBJECTIVES: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). METHODS: A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. RESULTS: At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). CONCLUSIONS: This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.

Correlation of skin blanching and percutaneous absorption for glucocorticoid receptor agonists by matrix-assisted laser desorption ionization mass spectrometry imaging and liquid extraction surface analysis with nanoelectrospray ionization mass spectrometry.

Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) and liquid extraction surface analysis (LESA) with nanoelectrospray ionization mass spectrometry (nESI-MS) have both been successfully employed to determine the degree of percutaneous absorption of three novel nonsteroid glucocorticoid receptor (GR) agonists in porcine ear sections. Historically, the ability of a glucocorticoid to elicit a skin blanching response when applied at low dose in ethanol solution to the forearms of healthy human volunteers has been a reliable predictor of their topical anti-inflammatory activity. While all three nonsteroidal GR agonists under investigation caused a skin blanching effect, the responses did not correlate with in vitro GR agonist potencies and different time courses were also observed for the skin blanching responses. MALDI MSI and LESA with nESI-MS were used to investigate and understand these different responses. The findings of the investigation was that the depth of porcine skin penetration correlates to the degree of skin blanching obtained for the same three compounds in human volunteers.