Enhancement of the haemostatic effect of platelets in the presence of high normal concentrations of von Willebrand factor

Introduction: Von Willebrand Factor (vWF) is a key protein mediating platelet adhesion on the surface of damaged endothelia. To the best of our knowledge, no trial exists that investigated the effect of platelet transfusion in combination with the administration of balanced vWF in severe blood loss, despite being widely used in clinical practice. The Basel Will-Plate study will investigate the impact of timely administration of balanced vWF (1:1 vWF and FVIII) in addition to platelet transfusion on need for blood and coagulation factor transfusion in patients admitted to the intensive care unit (ICU) who suffer from severe bleeding. The study hypothesis is based on the assumption that by adding balanced vWF to platelets will reduce the overall need of transfusion of blood products compared to transfusion of platelets alone. Methods and Analysis: The Will-Plate study is an investigator-initiated, single-centre, double-blinded randomised controlled clinical trial in 120 critically ill patients needing platelet transfusion. The primary outcome measure will be the number of fresh frozen plasma (FFP) and red blood cell (RBC) transfusions according to groups. Secondary outcome measures include number of platelet concentrates transfused within the first 48 h after treatment of study medication, quantity of blood loss in the first 48 hours after treatment with the study medication, length of stay in ICU and hospital, number of revision surgeries for haemorrhage control, ICU mortality, hospital mortality, 30-day mortality and one-year mortality. Patients will be followed after 30 days and 1 year for activities of daily living and mortality assessment. Sample size was calculated to detect a 50% reduction of the number of blood products subsequently transfused within two days in patients with Wilate® compared to placebo. Ethics and dissemination: This study has been approved by the Ethics Committee of Northwestern and Central Switzerland and will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as well as all national legal and regulatory requirements. Study results will be presented in international conferences and published in a peer-reviewed journal. Trials registration: ClinicalTrials.gov Identifier: NCT04555785 Protocol version: Clinical Study Protocol Version 2, 01.11.2020

Pharmacokinetics of cannabichromene in a medical cannabis product also containing cannabidiol and Δ9-tetrahydrocannabinol: a pilot study

Purpose Cannabichromene (CBC) is a phytocannabinoid commonly found in cannabis, yet its acute post-dose pharmacokinetics (PK) have not been examined in humans. This is a secondary data analysis from a trial investigating Spectrum Yellow oil, an oral cannabis product used for medical purposes that contained 20 mg cannabidiol (CBD), 0.9 mg Δ9-tetrahydrocannabinol (THC), and 1.1 mg CBC, per 1 mL of oil. Methods Participants (N = 43) were randomized to one of 5 groups: 120 mg CBD, 5.4 mg THC, and 6.6 mg CBC daily; 240 mg CBD, 10.8 mg THC, and 13.2 mg CBC daily; 360 mg CBD, 16.2 mg THC, and 19.8 mg CBC daily; 480 mg CBD, 21.6 mg THC, and 26.4 mg CBC daily; or placebo. Study medication was administered every 12 h for 7 days. Plasma CBC concentrations were analyzed by a validated two-dimensional high-performance liquid chromatography–tandem mass spectrometry assay. Results After a single dose and after the final dose, the Cmax of CBC increased by 1.3–1.8-fold for each twofold increase in dose; the tmax range was 1.6–4.3 h. Based on the ratio of administered CBD, THC, and CBC to the plasma concentration, the dose of CBD was 18 times higher than the dose of CBC, yet the AUC0–t of CBD was only 6.6–9.8-fold higher than the AUC0–t of CBC; the dose of THC was similar to the dose of CBC, yet THC was quantifiable in fewer plasma samples than was CBC. Conclusions CBC may have preferential absorption over CBD and THC when administered together. Trial Registration: Australian New Zealand Clinical Trials Registry #ACTRN12619001450101, registered 18 October 2019.

Hand Osteoarthritis: investigating Pain Effects of estrogen-containing therapy (HOPE-e): a protocol for a feasibility randomised placebo-controlled trial

Background Hand osteoarthritis (OA) is a common condition, causing pain, stiffness and reduced quality of life. Incidence is higher amongst women, particularly around the age of the menopause. Whilst the relationship between sex hormones and OA has been studied in vitro, in epidemiological studies and in clinical trials of hormone replacement therapy (HRT), this study is the first to investigate the effect of estrogen-containing therapy on hand pain in post-menopausal women with symptomatic hand OA in a randomised study design. Methods This is a feasibility study of a double-blinded placebo-controlled intervention with 1:1 randomisation to either a combination of conjugated estrogens 0.45 mg and bazedoxifene acetate 20 mg (Duavive) or placebo. The target population is post-menopausal women with symptomatic hand OA, aiming to recruit 60–90 study participants. The primary objective is to assess the feasibility of a future fully powered randomised controlled trial (RCT). Participants will take the study medication for 24 weeks and be followed up for 28 weeks after randomisation. The primary outcomes used to determine feasibility are eligible participant identification rates and routes; recruitment, randomisation and retention rates of eligible participants; study medication compliance; and the likelihood of unintentional unblinding. Secondary outcomes include measures of hand pain, function, appearance and menopausal symptoms. An end of study questionnaire and focus groups will help to refine the final protocol for a full study. Discussion Identifying new treatments for symptomatic hand OA is a recognised research priority. The study will help us to understand whether there are sufficient interested and eligible individuals in this target population who would consider HRT for their hand symptoms. It will provide proof-of-concept RCT data on the effects of HRT on hand pain and other clinically relevant outcomes in this population. The study will gain valuable information on the feasibility of a full RCT and how best to run this. The findings will be published in a peer-reviewed journal and presented at a relevant conference. Trial registration ISRCTN12196200 registered on 15 January 2019.

A phase II, open-label study to investigate the efficacy and safety of domatinostat in combination with avelumab in patients with advanced unresectable/metastatic Merkel cell carcinoma progressing on anti-PD-(L)1 antibody therapy: The MERKLIN 2 study.

TPS9592 Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive human skin cancer often caused by the Merkel cell polyomavirus or extended exposure to sunlight. Since the approvals of avelumab globally and subsequently pembrolizumab (US only), anti–PD–(L)1 antibody therapies have become the standard of care for advanced/metastatic MCC patients in recent years. Still, a significant proportion of MCC patients do not respond to or relapse on anti–PD–(L)1 antibody monotherapy. Recent preclinical data suggest that the small molecule, selective class I histone deacetylase inhibitor (HDACi) domatinostat can overcome critical mechanisms of MCC resistance to checkpoint inhibitors. These escape mechanisms include the epigenetic downregulation of the antigen processing and presentation machinery, hence treatment with domatinostat is thought to favorably modulate the tumor environment allowing a reintroduction of anti–PD–(L)1 therapy for an improved and sustained clinical benefit. Methods: The study is a phase II, multicenter, single arm clinical trial of the orally administered HDACi domatinostat in combination with the anti–PD–(L)1 antibody avelumab for patients with advanced unresectable/metastatic MCC that are progressing on previous anti–PD–(L)1 therapy. ClinicalTrials.gov Identifier: NCT04393753. Key Inclusion Criteria are: histologically confirmed MCC, an ECOG performance status ≤ 1, MCC in an advanced, unresectable stage III or metastatic stage IV, and progressing on previous anti–PD–(L)1 antibody monotherapy within the last 12 weeks before planned first administration of study medication. Key Exclusion Criteria are: history of serious anti–PD–(L)1 therapy related adverse reactions prohibiting further avelumab treatment, more than one line of previous systemic anti neoplastic therapy other than anti–PD–(L)1 antibody monotherapy (excluded: palliative radiation therapy of single lesions within 2 weeks before planned administration of study medication), significant active or chronic disease (infections, immunodeficiencies, cardiovascular, psychiatric disorders). A total of 40 patients will be enrolled in up to 46 clinical study sites in Europe and USA. Anti-tumor activity will be primarily assessed by the objective response rate according to RECIST v1.1 as an exploratory analysis. Secondary objectives include additional efficacy assessments, safety, quality of life and pharmacokinetics of domatinostat in combination with avelumab. Correlative aims include evaluating biomarkers for association with clinical benefit. The first patient was enrolled on Oct. 16, 2020, 21 of 46 clinical sites are active and 4 out of 40 planned patients have been enrolled as of Feb. 15, 2021. Clinical trial information: NCT04393753.

Are self-reported and self-monitored adherence good proxies for reaching relevant plasma concentrations?: Experiences from a study of anti-depressants in healthy volunteers

Background The use of electronic-based devices to measure and to improve adherence of subjects in clinical trials is increasing. AiCure has developed a mobile technology that is claimed to provide visual confirmation of drug ingestion. While there is evidence suggesting that including such self-monitoring device in a study increases adherence, the quality of the data produced by the device may be questionable. Can the mobile technology reliably distinguish whether a subject takes the study drug or not? Methods Adherence was calculated based on exposure, self-reporting and self-monitoring for subjects randomized to an anti-depressant. Levels of adherence and agreement between the three approaches were investigated based on calculation of proportions, two-way tables and receiver operating curves. Results A total of 214 subjects had measured concentrations of study drug at all three time points (end of weeks 3, 4 and 5), along with adherence data to define proportion of days adherent based on self-reporting and the self-monitoring instrument developed by AiCure. Self-reported adherence proportions were higher than self-monitored adherence proportions, although both were high (>90%). Neither self-reported and self-monitored adherence agreed with exposure-based adherence. Conclusion Both self-reported and self-monitored adherence overestimated adherence. Neither the self-reported nor the self-monitored adherence measure reflected subjects’ actual adherence. This prompts for cautiousness when interpreting either of them, and it underlines the need for thorough validation of electronic devices and software that claims to measure adherence. The AiCure instrument may not be able to reliably determine whether the subjects swallow the study medication.

339 Long-term Perception of Medication Effectiveness in Subjects Receiving Lemborexant for up to 12 Months

Introduction The Patient Global Impression–Insomnia version (PGI-I) is a self-report instrument used to evaluate a patient’s perception of the effects of their insomnia medication on their sleep relative to starting treatment. The PGI-I includes 3 items related to medication effects (helped/worsened sleep; decreased/increased time to fall asleep; and increased/decreased total sleep; responses include: 1=positive, 2=neutral, 3=negative) and 1 item related to perceived appropriateness of study medication strength (responses include: 1=too strong, 2=just right, 3=too weak). In Study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), significantly greater percentages of subjects reported a positive impact of the dual orexin receptor antagonist lemborexant (LEM) versus placebo (PBO) at 1, 3, and 6mo for each of the PGI-I items related to medication effects. PGI-I results at 9 and 12mo are presented here for subjects that received continuous treatment with LEM for up to 12mo. Methods Study 303 was a 12-mo, randomized, double-blind, PBO-controlled (first 6mo [Period 1]), phase 3 study. Subjects were aged ≥18y with insomnia disorder. During Period 1, subjects received PBO (n=318) or LEM (5mg, [LEM5], n=316; 10mg, [LEM10], n=315). During Period 2 (second 6mo), LEM subjects continued their assigned dose while PBO subjects were rerandomized to LEM5 or LEM10 (reported separately). Subjects were also administered the PGI-I at months 9 and 12. Results At 9 and 12mo, the majority of LEM5 (9mo, n=241; 12mo, n=205) and LEM10 (9mo, n=211; 12mo, n=192) subjects reported that their study medication “helped” sleep at night (9mo: LEM5=73.4%; LEM10=76.3%; 12mo: LEM5=74.6%; LEM10=77.6%), reduced time to fall asleep (9mo: LEM5=79.3%, LEM10=78.2%; 12mo: LEM5=76.6%, LEM10=80.2%), and increased total sleep time (9mo: LEM5=62.2%, LEM10=73.0%; 12mo: LEM5=62.4%; LEM10=65.1%). Also, at both 9 and 12mo, the majority of subjects in the LEM5 and LEM10 groups, responded that treatment strength was “just right” (9mo: LEM5=60.6%, LEM10=62.1%; 12mo: LEM5=63.4%; LEM10=60.4%). LEM was well tolerated. Most adverse events were mild or moderate. Conclusion The majority of subjects receiving LEM5 or LEM10 reported a positive medication effect at both 9 and 12mo, sustaining similar positive effects for LEM achieved earlier, during the first 6mo of treatment in Study 303. Support (if any) Eisai Inc.

DOP53 Pregnancy outcomes in the ozanimod clinical development program in relapsing multiple sclerosis, Ulcerative Colitis, and Crohn’s Disease

Background Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, has demonstrated efficacy in patients with relapsing multiple sclerosis (rMS) and ulcerative colitis (UC), and is being studied in Crohn’s disease (CD). S1P1-3 receptors are involved in vascular formation during embryogenesis. Within studies in the ozanimod clinical development program, female participants of childbearing potential were required to use effective contraception while receiving and up to 3 months after discontinuing ozanimod; treatment discontinuation was required if pregnancy was confirmed. Here we review pregnancy outcomes data with ozanimod use in rMS, UC, and CD. Methods All pregnancies, including participant and partner pregnancies, in the ozanimod clinical development program with an initial diagnosis prior to a cut-off date of September 30, 2020 were assessed for pregnancy outcomes. Results At cut-off, safety data on 4131 participants were available. A total of 83 pregnancies were reported in the safety database of participants treated with ozanimod or their partners (Table). All pregnancy exposures occurred during the first trimester. Of the 60 pregnancies in ozanimod clinical trials, 9 were reported in patients with UC, and 3 in patients with CD. Participants discontinued study medication promptly except for those who elected pregnancy termination and did not discontinue study medication. Among all pregnancies in the ozanimod clinical development program, the incidence of spontaneous abortion in clinical trial participants was 15%; the rate in the general population is between 12% and 22%. The rate of preterm birth was 10.7% of live births; as reference, the global population estimate is 10.6% and the European estimate is 8.7%. No teratogenicity was observed. Outcomes in patients with UC included 2 live births that resulted in 2 full-term healthy newborns, 2 ongoing pregnancies, 2 spontaneous early losses, and 3 elective terminations. Conclusion While pregnancy should be avoided in patients on and 3 months after stopping ozanimod and clinical experience with ozanimod during pregnancy is limited, there has been no increased event of foetal abnormalities or adverse pregnancy outcomes seen with ozanimod exposure in early pregnancy.

Effect of prazosin on feline recurrent urethral obstruction

Objectives The aim of this study was to determine if male cats treated with 7 days of prazosin following relief of urethral obstruction (UO) experienced decreased rates of recurrent urethral obstruction (rUO) within 30 days vs those treated with 7 days of placebo. Methods All castrated male cats presenting for the first time with UO from May 2014 to August 2017 were eligible for enrollment. Exclusion criteria included the administration of medications or passage of a urinary catheter prior to referral, the presence of heart disease or hypertension requiring medication, prior treatment with glucocorticoids, non-steroidal anti-inflammatory medications, prazosin or phenoxybenzamine, or radiographic identification of cystoliths. Cats were treated with standardized anesthetic and analgesic protocols, standardized indwelling urinary catheter management, and were hospitalized for care. A random numbers table was generated prior to study initiation and cats were randomized to receive either prazosin (0.5 mg PO q12h for 7 days) or placebo in a blinded fashion. A 30-day follow-up with owners via telephone was performed to identify the rate of rUO. Cats that did not receive the full course of study medication were removed from the analysis. The study was unblinded at the end of data collection. Results Eighty cats were enrolled and 65 cats completed the study; 12 were excluded because they did not receive the study medication. Sixteen of 65 cats experienced rUO (25%). Of the 16 cats experiencing rUO, five received placebo (n = 5/28 [18%]) and 11 received prazosin (n = 11/37 [30%]). Ten of the cats that experienced rUO reblocked while still hospitalized. There was no significant difference in frequency of rUO in cats treated with prazosin vs placebo ( P = 0.27). Conclusions and relevance Prazosin administered at 0.5 mg PO q12h did not decrease the rate of rUO in this population of obstructed male cats vs placebo. These results further support evidence suggesting that prazosin may not be beneficial in prevention of feline rUO.