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No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant—an orally administered small molecule CGRP receptor antagonist—with placebo in the acute treatment of migraine among adults in these countries. This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran–Mantel–Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed. 1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4–13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6–20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events. Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. BioShin Limited. For the Chinese and Korean translations of the abstract see Supplementary Materials section.

BackgroundHypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT).ObjectiveTo investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT.MethodsMITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort.ResultsAn increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p=0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p=0.006) for subjects with a higher number of elevated T2 biomarkers.ConclusionsHDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype.Trial registration number NCT01433523.

Immune Cell Deconvolution methods utilizing gene expression profiling to quantify immune cells in tissues and blood are an appealing alternative to flow cytometry. Our objective was to investigate the applicability of deconvolution approaches in clinical trial settings to better investigate the mode of action of drugs for autoimmune diseases. Popular deconvolution methods CIBERSORT and xCell were validated using gene expression from the publicly available GSE93777 dataset that has comprehensive matching flow cytometry. As shown in the online tool , ~ 50% of signatures show strong correlation (r > 0.5) with the remainder showing moderate correlation, or in a few cases, no correlation. Deconvolution methods were then applied to gene expression data from the phase III CLARITY study (NCT00213135) to evaluate the immune cell profile of relapsing multiple sclerosis patients treated with cladribine tablets. At 96 weeks after treatment, deconvolution scores showed the following changes vs placebo: naïve, mature, memory CD4 + and CD8 + T cells, non-class switched, and class switched memory B cells and plasmablasts were significantly reduced, naïve B cells and M2 macrophages were more abundant. Results confirm previously described changes in immune cell composition following cladribine tablets treatment and reveal immune homeostasis of pro- vs anti-inflammatory immune cell subtypes, potentially supporting long-term efficacy.

The acute diarrhea is a wide-spread disease. The prescription of enterosorbents is appropriate as a primary measure for the treatment of the acute diarrhea for effective prevention of the fluid and electrolyte loss, as well as method for symptom relief of the attack of the disease. Aim of the study - the antidiarrheal efficacy and safety study of high-dispersion silicon dioxide enterosorbent in tablet dosage form in patients with acute diarrhea. This was randomized, double-blind, placebo-controlled, 4-center study. Acute diarrhea was defined as three and more episodes of watery stool per day either during 48 hours or less before study entry in the patients having normal stool recently. It has been postulated that symptoms and signs of acute diarrhea have to be caused by direct infection of the gastrointestinal tract and did not associated with moderate-to-severe systemic states. 144 patients with established acute diarrhea were randomized into treatment group (enterosorbent “Carbowhite”, n = 120) or placebo group. Date collection including severity diarrhea, systemic symptoms was performed at baseline and daily during 7 days. Stool examination and serological assay were performed at baseline. The primary end points were declared as time to complete recovery from acute diarrhea. It has been found that the use of the siliceous enterosorbent (“Carbowhite”) allowed to reduce (p < 0.001) the treatment period averagely for 0.9 days (95% confidence interval 0.5–1.2 days) in comparison with placebo. Data of safety monitoring has revealed that both patient groups had negative stool culture, while initiation of antibiotic treatment was run more frequently in placebo group (8.3%) compared to investigational product group (4.1%, P = 0.044). The siliceous enterosorbent “Carbowhite” was well tolerated and reduced the recovery time of the acute episode of the diarrhea in the clinically significant form.

SummaryIn this phase 1 open-label study, we assessed the relative bioavailability of a prototype tablet formulation of TAK-931, a cell division cycle 7 kinase inhibitor, in reference to the current powder-in-capsule (PIC) formulation in patients with advanced solid tumors for whom no effective standard treatment was available. Adult patients were randomized 1:1 in a crossover fashion to receive one dose of TAK-931 80 mg PIC on Day 1 and one dose of TAK-931 80 mg tablet on Day 3 (or the reverse sequence), followed by TAK-931 50 mg PIC once daily (QD) for 12 days starting from Day 5, before a 7-day rest period (Cycle 0). From Cycle 1, all patients received 50 mg PIC QD on Days 1–14 followed by a 7-day rest period. Twenty patients were enrolled. Median Tmax was achieved approximately 2 h post-dose of TAK-931 80 mg for both tablet and PIC. Geometric mean Cmax, AUC exposures, and T1/2z of TAK-931 were similar for both formulations. Geometric mean Cmax, AUClast, and AUCinf ratios were 0.936 (90% confidence interval [CI]: 0.808–1.084), 1.004 (90% CI: 0.899–1.120), and 1.007 (90% CI: 0.903–1.123), respectively, for TAK-931 tablet in reference to PIC. Discontinuation of TAK-931 due to treatment-emergent adverse events (TEAEs) occurred in 1 patient. Four (20%) patients experienced a serious TEAE; none were considered related to TAK-931. Pharmacokinetics and systemic exposure profiles were similar following administration of both formulations, supporting the transition from PIC to tablet in the clinical development of TAK-931. (Trial registration numberClinicalTrials.gov NCT03708211. Registration date October 12, 2018).

Background Infestation with Sarcoptes scabiei in dogs is a debilitating disease if left untreated and is transmissible to humans. Two field studies were conducted to confirm the efficacy of orally administered sarolaner in combination with moxidectin and pyrantel (Simparica Trio ® ) in the treatment of sarcoptic mange in dogs. Methods Client-owned dogs with S. scabiei infestation were enrolled and received 2 monthly treatments. In the first, small-scale study, 12 dogs each were allocated randomly to treatment with either placebo or Simparica Trio ® . Skin scrapings to detect live mites and assessment of clinical signs of sarcoptic mange were conducted on Days 0, 14, 30, 44, and 60. Efficacy was calculated based on the percent reduction in arithmetic mean live mite counts relative to placebo. In the second, large-scale study, 75 dogs were allocated randomly to treatment with Simparica Trio ® and 37 to treatment with afoxolaner + milbemycin oxime (NexGard Spectra ® ). Skin scrapings to detect live mites and assessment of clinical signs of sarcoptic mange were conducted on Days 0, 14, 30, and 60. The parasitological cure rate (percentage of dogs without live mites) was determined and non-inferiority of Simparica Trio ® to the control product was assessed. Results In the small-scale study, 2 monthly doses of Simparica Trio ® resulted in a significant reduction ( P  ≤ 0.0050) in live S.   scabiei mite numbers and provided a 99.2% reduction relative to placebo by Day 60. Clinical signs of sarcoptic mange improved throughout the study in Simparica Trio ® -treated dogs. In the large-scale study, the parasitological cure rate on Days 30 and 60 was 97.3% and 100% in the Simparica Trio ® group and 91.9% and 100% in the afoxolaner + milbemycin oxime group, respectively. The parasitological cure rate for Simparica Trio ® was non-inferior to afoxolaner + milbemycin oxime at both time points. Clinical signs of sarcoptic mange improved throughout the study in both groups. Conclusions Two-monthly doses of Simparica Trio ® reduced S. scabiei mite counts by 99.2% relative to placebo in one study and eliminated S. scabiei mites in 100% of dogs in the second study, thus confirming that Simparica Trio ® is highly effective in the treatment of sarcoptic mange in dogs caused by S. scabiei var. canis. Graphical abstract

Background Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. Methods Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. Results Overall, 1075 participants (rimegepant, n  = 538; placebo, n  = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p  = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p  <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. Conclusions A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. Trial registration Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05. Graphical Abstract

Background Aphthous stomatitis is one of the most common oral mucosal diseases. Due to the commonness of recurrent aphthous stomatitis and considering the anti-inflammatory, analgesic, and tissue regenerative properties of atorvastatin and the lack of a study on the effect of statins on minor recurrent aphthous stomatitis, this study investigates the effect of atorvastatin mucoadhesive tablets as a topical treatment on reduction of symptoms and duration of this disease. Methods This study is a randomized, double-blinded clinical trial. Patients were divided into two groups, atorvastatin and, placebo; each of the patients received three mucoadhesive tablets daily in the morning, noon, and night. Finally, the patients were examined on days 0 (baseline), 3, 5, and 7 to determine the diameter of the inflammatory halo. The VAS scale was used to evaluate pain intensity for up to 7 days after each meal. The data was entered into SPSS 24 software and analyzed. Results The halo diameter did not significantly differ between the two groups on baseline (P > 0.05). However, on the study’s third, fifth, and seventh days, the difference between the two groups was remarkable, so in the atorvastatin group, the size of the lesions decreased in shorter healing time (P < 0.05). In addition, the patient’s pain intensity (VAS) also showed a significant decrease in the atorvastatin group except on the first, second, and seventh days of the study (P < 0.05). Conclusion Atorvastatin mucoadhesive tablets effectively reduce the pain of patients with minor recurrent aphthous stomatitis and reduce the size and healing time of the lesions, so their application should be considered in treating minor recurrent aphthous stomatitis. The present study was approved by the Medical Ethics Committee of Mazandaran University of Medical Sciences with the ethics code IR.MAZUMS.REC.1400.8346. Also, this study received code IRCT20170430033722N4.

Background A novel budesonide orodispersible tablet (BOT) has been proven effective in adult patients with active eosinophilic oesophagitis (EoE) in a 6‐week placebo‐controlled trial (EOS‐1). Aims To report the efficacy of an open‐label induction treatment with BOT in a large prospective cohort of EoE patients within the EOS‐2 study. Methods Patients with clinico‐histological active EoE were treated with BOT 1 mg BID for 6 weeks. The primary endpoint was clinico‐histological remission (≤2 points on numerical rating scales [0–10] each for dysphagia and odynophagia, and peak eosinophil count <16 eos/mm2 hpf (corresponds to <5 eos/hpf)). Further study endpoints included clinical and histological remission rates, change in the EEsAI‐PRO score, change in peak eosinophil counts, and deep endoscopic remission using a modified Endoscopic Reference Score. Results Among 181 patients enrolled, 126 (69.6%) achieved clinico‐histological remission (histological remission 90.1%, clinical remission 75.1%). The mean peak eosinophil counts decreased by 283 eos/mm2 hpf (i.e., by 89.0%). Mean EEsAI‐PRO score decreased from baseline by 29 points and deep endoscopic remission was achieved in 97 (53.6%) patients. The majority of patients judged tolerability as good or very good (85.6%) and compliance was high (96.5%). Local candidiasis was suspected in 8.3% of patients; all were of mild severity, resolved with treatment and none led to premature withdrawal from the study. Conclusions In this large prospective trial, a 6‐week open‐label treatment with BOT 1 mg BID was highly effective and safe in achieving clinico‐histological remission of active EoE and confirmed the results of the placebo‐controlled EOS‐1 trial.

Background A pivotal randomised, blinded, positive-controlled, multicentre, European field study was conducted to evaluate the effectiveness and safety of a novel combination tablet of lotilaner and milbemycin oxime (Credelio ® Plus) administered orally to client-owned dogs naturally infested with fleas and/or ticks. Methods In this field study, households with flea- or tick-infested dog(s) were enrolled on Day 0 into the study to provide data for either the tick or flea infestation cohorts. Households were randomised in a 2:1 ratio to receive either the combination investigational product (IP, Credelio Plus ® tablets) or the control product (CP: Nexgard Spectra ® tablets). Dogs were administered IP (flea cohort n  = 135; tick cohort: n  = 147) or CP (flea cohort: n  = 67; tick cohort: n  = 74) once every 4 weeks for a total of three times at a dose rate of 20.0–41.5 mg/kg bodyweight lotilaner and 0.75–1.53 mg/kg bodyweight milbemycin oxime (IP) or as recommended (CP). Percentage reduction was calculated by comparing individual dog flea and tick counts at each assessed post-treatment time point to their respective baseline (pre-treatment) infestation. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea-allergic dogs on the days that flea counts were performed. Results Flea effectiveness of Credelio Plus ® after 3 consecutive monthly treatments was 100% against Ctenocephalides felis , C. canis and Pulex irritans . Tick effectiveness of Credelio Plus ® over the same time frame was 99.3% for Ixodes ricinus and 100% against Rhipicephalus sanguineus ( s.l. ). Flea effectiveness of the CP after three consecutive monthly treatments was 100% against C. felis , C. canis and P. irritans . Tick effectiveness of the CP over the same time frame was 99.8% for I. ricinus and 100% against R. sanguineus . Credelio Plus ® was well tolerated based on the safety assessments in all treated dogs in this field study. Within both treatment groups there was a reduction in total FAD scores from baseline. Conclusions This pivotal European field study demonstrated the excellent effectiveness and safety of a combination of lotilaner and milbemycin oxime (Credelio Plus ® ) administered orally to dogs naturally infested with fleas and/or ticks. Graphical Abstract