CDT for acute PAO with alfimeprase was as safe as placebo. However, alfimeprase was no more effective than placebo in increasing 30-day surgery-free survival. The surprising effectiveness of placebo alone demonstrates that the inclusion of a placebo arm is essential to the design of future lytic trials.

Background: Chronic pruritus causes major morbidity in epidermolysis bullosa (EB). The substance P-neurokinin 1 receptor (SP-NK1) pathway is a promising target for treating EB-related pruritus.Objective: To evaluate the safety and efficacy of the oral NK1 receptor antagonist serlopitant in treating moderate-severe pruritus in EB. Methods:The study randomized 14 patients to serlopitant or placebo for 8 weeks, followed by a 4-week washout and optional open-label extension. The primary end point was change in itch as measured by the Numeric Rating Scale. Secondary end points were change in itch during dressing changes and wound size. Results:We observed greater itch reduction with serlopitant, equivalent to a 0.64-point comparative reduction on the 11-point Numeric Rating Scale by week 8, although this failed to meet statistical significance (P = .11). More serlopitant patients achieved $3-point reduction compared with placebo (43% vs 14%, P = .35). In post hoc analysis excluding 1 patient with a concurrent seborrheic dermatitis flare, serlopitant achieved significantly greater median itch reduction from baseline by week 4 (À2 points vs 0, P = .01). We observed no statistically significant differences in secondary end points. Serlopitant was welltolerated.Limitations: Small sample size due to disease rarity. Conclusion:The potential itch reduction with serlopitant observed in this trial will be pursued by a larger powered trial (NCT03836001).

STUDY QUESTION Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss? SUMMARY ANSWER rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss. WHAT IS KNOWN ALREADY The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates. STUDY DESIGN, SIZE, DURATION A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK. PARTICIPANTS/MATERIALS, SETTING, METHODS One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte – colony stimulating factor 130 μg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat. MAIN RESULTS AND THE ROLE OF CHANCE A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29–34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26–33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7–1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) par...

Patients with moderate-to-severe atopic dermatitis (AD) have a high unmet need for safe chronic therapies. IL-22 was suggested to have a pathogenic role in AD, but human data are lacking. In a proof-of-concept, randomized placebo-controlled phase 2a trial in 60 patients, an anti-IL-22mAb (fezakinumab/ILV-094) showed clinical benefit in severe AD. Progressive clinical improvements extended beyond the last dose (10wks) until end-of-study (20wks). Skin biopsy analyses were performed at 0, 4, 12wks, by transcriptomic and immunohistochemistry analyses. Changes in the AD transcriptome were estimated by differentially expressed genes/DEGs criteria of 2-fold change and false discovery rate <0.05 in lesional vs. non-lesional skin. Greater changes in the AD gene-fingerprinting were seen with fezakinumab, as compared to placebo (25.3% and 65.5% vs 10.5% and 13.9% at 4 and 12wks, respectively). Since IL-22 blockade only shows significant efficacy in severe AD, we used median IL-22 expression at baseline to stratify for high (n¼30) and low (n¼29) IL-22expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-group (82.8% and 139.4% at 4 and 12wks, respectively), than in the respective IL-22-high placebo (39.6% and 56.3% at 4 and 12wks; p<10-9 drug vs placebo). Significant downregulations of key inflammatory axes, including Th1/CXCL9, Th2/ CCL18, CCL22, Th17/CCL20, DEFB4A, and Th22/IL-22, S100As-related markers were restricted to the high-IL-22 group (p<0.05). We also defined a set of baseline predictors of response, mostly involving T-cell and dendritic-cell genes. This is the first human report showing profound effects of IL-22 blockade in AD skin, particularly in patients with high-IL-22. These data suggest a central role for IL-22 in AD, and the need for a precision medicine approach for improving therapeutic outcomes.

ObjectThe NT‐04 clinical trial of investigational medication NT100 had a limited, though geographically diverse, study population. To enhance potential birth defect identification, photographic dysmorphology exam of infants was performed along with review of prenatal and postnatal medical records.MethodsStandardized photographic views were developed: full body (prone and supine), face, both profiles, dorsal and ventral hands and feet, genitalia, and birthmarks/skin lesions. Professional photographers were identified and trained. Photos were taken in the first month of life at the subject's home and uploaded to a secure electronic online photo viewer. The evaluating geneticist accessed the photos electronically and submitted an evaluation.ResultsForty subjects had 39 evaluable outcomes (55 babies). Twelve photographers were recruited, 10 of whom worked with multiple subjects. Photographic dysmorphology evaluation was done on 38 pregnancy outcomes. Only one baby had missing photos due to an apparent protocol error. Four babies were photographed with diaper on.ConclusionsThe standardized photographs worked well. Advantages include: a single clinician evaluating all infants, the photographs could be reviewed repeatedly as needed, and minor malformations were more uniformly identified. Difficulties were: identifying local photographers and supplying training and training materials. There was no protocol for retaking or obtaining new photos and the study consent form did not include permission to publish the photographs. This was a successful pilot study of infant photographic assessment to detect congenital anomalies in a clinical trial.