Once Daily Research Articles

237-OR: Insulin Icodec: An Insulin Analog Suited for Once-Weekly Dosing in Type 2 Diabetes

Insulin icodec* is a novel basal insulin analog designed for single once-weekly (OW) subcutaneous injection. This randomized, double–blind, double–dummy trial investigated the pharmacokinetics (PK), pharmacodynamics (PD) and safety of insulin icodec. Fifty individuals with type 2 diabetes (insulin treated±metformin; 43 men; mean±SD age 57±5 years, BMI 30.1±2.7 kg/m2, A1C 7.4±0.6%) received OW insulin icodec (12, 20 or 24 nmol/kg) plus once–daily (OD) placebo (N=13, 13, 12) or OD insulin degludec (0.4 U/kg) plus OW placebo (N=12) for 5 weeks in 3 dose level cohorts. PD properties were investigated at close to steady state in 24-h glucose clamps on days 2 and 7 after the last insulin icodec dose. Median tmax,insulin icodec was 16 h and geometric mean t½,insulin icodec was 196 h with no systematic differences between dose levels. The glucose–lowering effect over a weekly dosing interval was derived from the observed PK/PD data using a PK/PD model and showed close to even distribution over the 7 days across all dose levels (Figure). The adverse event (AE) incidence did not increase with increasing insulin icodec dose (100%, 69%, 75%, respectively). There were no serious or severe AEs, severe hypoglycemic episodes or injection site reactions. In conclusion, insulin icodec was safe and well-tolerated and showed PK/PD properties supporting once-weekly administration at clinically relevant dose levels. * Proposed INN. Disclosure U. Hövelmann: None. L. Brøndsted: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. N.R. Kristensen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. R. Ribel-Madsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J. DeVries: Advisory Panel; Self; Novo Nordisk A/S, Zealand Pharma A/S. Consultant; Self; Metronom Health. Employee; Self; Profil Institute for Clinical Research. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. H. Haahr: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Novo Nordisk

Personalized combination of neoadjuvant domatinostat, nivolumab and ipilimumab in macroscopic stage III melanoma patients stratified according to the interferon-gamma signature: The DONIMI study.

TPS10087 Background: Previous OpACIN and OpACIN-neo studies, investigating neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO), demonstrated high pathologic response rates (74-78%) and favorable long-term outcomes in patients (pts) achieving pathologic response; at 36 and 18 months follow-up, respectively, only 1/71 (1.4%) pts with response has relapsed. In contrast, pts without pathologic response (pNR) have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline interferon-gamma (IFN-γ) signature low pts were less likely to respond to neoadjuvant IPI plus NIVO. The DONIMI study tests the combination of NIVO +/- IPI with domatinostat (DOM), a class 1 histone deacetylase inhibitor, according to the IFN-γ signature in the tumor. Based on the signature previously described by Ayers et al. we have developed a neoadjuvant IFN-γ signature algorithm that will be used for the first time to classify pts in this prospective trial. Methods: The aim of this two-center investigator-initiated phase 1b study is to assess the safety and feasibility of neoadjuvant NIVO +/- DOM +/- IPI in 45 stage III melanoma pts with RECIST 1.1 measurable de-novo or recurrent disease. IFN-γ signature high pts (n = 20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240mg q3wk) or Arm B (2 cycles NIVO 240mg q3wk + DOM 200mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n = 25) will be randomized to Arm C (2 cycles NIVO 240mg q3wk + DOM 200mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240mg q3wk + IPI 80mg q3wk + DOM 200mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200mg BID, d1-14, q3wks), a lower dosing scheme (100mg OD, d1-14, q3wks) or the same dosing scheme (200mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 pts cannot adhere to the preplanned time of surgery (week 6 +/- 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. The first patient was enrolled on January 23th, 2020. Clinical trial information: NCT04133948.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism

Anticoagulant plasma concentrations and patient characteristics might affect the benefit–risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN–DVT and EINSTEIN–PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure–response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure–efficacy relationships were shallow. Exposure–safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit–risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

Expected and Observed Glomerular Filtration Rates in Kidney Transplant Patients Converted to Once Daily Tacrolimus: 10 Years of Follow-up

The decline of allograft kidney function in the long term remains a significant issue in renal transplantation, with drug nephrotoxicity and cardiovascular complications as important risk factors. Our study aimed to evaluate the estimated glomerular filtration rate (eGFR) trend and metabolic cardiovascular risk factors over 10 years in a cohort of kidney transplant (KT) recipients converted from twice-daily (TD) tacrolimus (Tac) to once-daily (OD)-Tac.We enrolled 55 consecutive KT recipients who had been at the outpatient clinic between 2009 and 2011. Thirty-seven reached the 10-year follow-up. We compared the observed eGFR with the expected eGFR trend described in KT-recipients and monitored blood pressure and metabolic cardiovascular risk factors.The observed eGFR remained stable throughout the complete follow-up (P = .188). The observed decline of eGFR was significantly lower compared with the expected decline for KT patients (P < .001). The blood pressure was maintained within target values. The monitoring of plasma glucose levels demonstrated the stability of median values (P = .686), as well as cholesterol level (P = .250), high-density lipoprotein (HDL) cholesterol (P = .294), and triglycerides (P = .592) throughout the follow-up. The monitoring of tacrolimus plasma level demonstrated that median trough levels remained constant (median values 4.4-5.5 ng/mL) throughout the entire follow-up period (P = .149). We suggest that the reasonable control of metabolic risk factors for cardiovascular disease over long-term follow-up may significantly contribute to the preservation of eGFR compared with the decline expected in KT recipients.

Gentamicin and amikacin adversely affect male infertility indicated by pharmacological, andrological and pathological evidence

Background: Many drugs are implicated in male infertility and screening for medication history is an important for diagnosis and treatment of the problem. The aim is to study amikacin effect on male reproductive system in comparison to gentamicin.Methods: Twenty-five male wister rats weighted 220±20 gm and aged 8 weeks were randomly divided into five groups of five. The first group received gentamicin in dose 18.25 mg/kg/day once daily (OD) (therapeutic dose). The second group received gentamicin with double dose of the first group. The third group received amikacin in dose 54.75 mg/kg/day OD (therapeutic dose). The Fourth group received amikacin with double dose of the third group. However, the fifth group served as a control and received normal saline (NS) OD. All treatments were administered intraperitoneally (IP) for 14 days. On the 15th day, blood samples and reproductive organs were obtained from all animals. Testicular tissues were prepared for genetic testing and chemical and microscopical examination.Results: Amikacin and gentamicin negatively affected reproductive organs weights, sperm parameters, serum follicle stimulating hormone and luteinizing hormone (LH) level relative to control (p&lt;0.05). However, serum testosterone level was only affected with gentamicin (p&lt;0.05). A significant difference between gentamicin and amikacin was found in sperm count, testis and epididymis weights and serum testosterone and LH level (p&lt;0.05). Testicular histopathological changes were also found with the two drugs with different degrees. Effects of both gentamicin and amikacin were dose-dependent.Conclusions: Both gentamicin and amikacin adversely affect andrological function that should be monitored and controlled during application of these drugs.

Ciprofloxacin and levofloxacin adversely affect male infertility indicated by pharmacological, andrological and pathological evidence

Background: Drug-induced reproductive organs toxicities is an important aetiology in investigation of male infertility. The aim is to study levofloxacin effect on male reproductive system in comparison to ciprofloxacin.Methods: Twenty-five male wister rats weighted 230±20 gm and aged 8 weeks were randomly divided into five groups of five. The first group received ciprofloxacin with dose 78.23 mg/kg/day in 2 doses (therapeutic dose). The second group received the double dose of the first group ciprofloxacin. The third group received levofloxacin with dose 39.11 mg/kg/day once daily (OD) (therapeutic dose). The Fourth group received the double dose of the third group levofloxacin. However, the fifth group served as a control and received normal saline with carboxymethylcellulose OD. All treatments were administered orally for 14 days. On the 15th day, blood samples and reproductive organs were obtained from all rats. Testicular tissues were prepared for genetic testing and chemical and microscopical examination.Results: Ciprofloxacin and levofloxacin negatively altered reproductive organ weights, sperm parameters and serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) level (p&lt;0.05). Additionally, serum testosterone level was significantly deceased in ciprofloxacin-treated group (the double dose) (p&lt;0.05) relative to control. The difference between ciprofloxacin and levofloxacin was significant in seminal vesicle weight and serum LH and FSH level (p&lt;0.05). Testicular histopathological changes were also found with the two drugs with different degrees. Effects of levofloxacin and ciprofloxacin were dose-dependent.Conclusions: Both ciprofloxacin and levofloxacin adversely affect andrological function that should be monitored and controlled during application of these drugs.

Aspirin, clopidogrel and prasugrel monotherapy in patients with type 2 diabetes mellitus: a double-blind randomised controlled trial of the effects on thrombotic markers and microRNA levels

BackgroundDespite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM.Materials and methods56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions.ResultsOf the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20μmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 μmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 μg/mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083).ConclusionsPrasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM.Trial registration EudraCT, 2009-011907-22. Registered 15 March 2010, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011907-22/GB.

Rivaroxaban in patients with mechanical heart valves: A pilot study

BackgroundPatients with mechanical heart valves are still not eligible for treatment with direct oral anticoagulants (DOAC). We aimed to conduct a proof-of-principle study investigating the anti-Xa inhibitor rivaroxaban as antithrombotic treatment in patients with recent mechanical aortic valve replacement. Materials and methodsLow-risk patients scheduled for elective mechanical aortic valve replacement were treated with rivaroxaban 20 mg once daily (OD) in a prospective cohort study, started on day 3 postoperatively and given for 6 months. The study was registered at ClinicalTrials.gov (#NCT02128841). ResultsTen patients were included (median age, 48; range 39 to 60). Indication was aortic valve stenosis in 6 patients, aortic root aneurysm with severe aortic valve regurgitation in 3 patients, and mixed stenosis/regurgitation in 1 patient. Neither thromboembolic nor bleeding events were observed, and no patient died. Absence of valve thrombosis was demonstrated in all patients. On day 7, median D-dimers were 2723 μg/L (inter-quartile range [IQR] 1672, 5695 μg/L), median TAT levels were 4.5 μg/L (IQR 4.1, 5.6 μg/L); and median peak thrombin generation was 150 nM (IQR 91, 183). On day 90, median D-dimers were 426 μg/L (IQR 278, 569), median TAT levels were 2.7 μg/L (IQR 2.2, 3.1), and median peak thrombin generation were 66 nM (IQR 62, 87). ConclusionsRivaroxaban 20 mg OD was safe and effective in a pilot study of 10 low risk patients with mechanical aortic heart valve. Our results justify larger studies investigating the application of anti-Xa inhibitors in patients with mechanical heart valves.

Frequency of Screening and SBT Technique Trial - North American Weaning Collaboration (FAST-NAWC): a protocol for a multicenter, factorial randomized trial

RationaleIn critically ill patients receiving invasive mechanical ventilation (MV), research supports the use of daily screening to identify patients who are ready to undergo a spontaneous breathing trial (SBT) followed by conduct of an SBT. However, once daily (OD) screening is poorly aligned with the continuous care provided in most intensive care units (ICUs) and the best SBT technique for clinicians to use remains controversial.ObjectivesTo identify the optimal screening frequency and SBT technique to wean critically ill adults in the ICU.MethodsWe aim to conduct a multicenter, factorial design randomized controlled trial with concealed allocation, comparing the effect of both screening frequency (once versus at least twice daily [ALTD]) and SBT technique (Pressure Support [PS] + Positive End-Expiratory Pressure [PEEP] vs T-piece) on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American ICUs. In the OD arm, respiratory therapists (RTs) will screen study patients between 06:00 and 08:00 h. In the ALTD arm, patients will be screened at least twice daily between 06:00 and 08:00 h and between 13:00 and 15:00 h with additional screens permitted at the clinician’s discretion. When the SBT screen is passed, an SBT will be conducted using the assigned technique (PS + PEEP or T-piece). We will follow patients until successful extubation, death, ICU discharge, or until day 60 after randomization. We will contact patients or their surrogates six months after randomization to assess health-related quality of life and functional status.RelevanceThe around-the-clock availability of RTs in North American ICUs presents an important opportunity to identify the optimal SBT screening frequency and SBT technique to minimize patients’ exposure to invasive ventilation and ventilator-related complications.Trial registrationClinical Trials.gov, NCT02399267. Registered on Nov 21, 2016 first registered.

A prospective phase I multicentre randomized cross-over pharmacokinetic study to determine the effect of food on abiraterone pharmacokinetics

PurposeAbiraterone acetate is used at a fixed oral dose of 1000 mg once daily (OD) taken fasted. By administering abiraterone acetate with food, a reduced dose can potentially be given while maintaining equivalent abiraterone exposure. Moreover, administering abiraterone acetate with a breakfast is considered more patient friendly. The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast (CB) compared to the standard intake of 1000 mg OD fasted.MethodsIn this phase I, randomized cross-over, multi-center study, abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic castration-resistant prostate cancer who were treated for 14 days with 1000 mg abiraterone acetate taken fasted, followed by 14 days of treatment with 500 mg taken with a CB.Results14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. The geometric mean ratio (GMR) (fed/fasted) was 0.88 (90% CI 0.73–1.07) for area-under-the-curve (AUC0–24h), 1.03 (90% CI 0.79–1.34) for Cmax and 0.81 (90% CI 0.60–1.10) for Ctrough, respectively. High inter-patient variability (> 50%) was found for all PK parameters under both intake conditions. Patients seemed to be slightly more satisfied about the intake of 500 mg abiraterone acetate when taken with a CB compared to 1000 mg fasted.ConclusionIn conclusion, a bioequivalent lower dose of abiraterone taken with food could not be established in our study. Although based on the absence of a exposure–toxicity relationship, the strict bioequivalence margins as defined by the FDA guidelines could be applied more flexible for abiraterone. Information on the effect of food on abiraterone pharmacokinetics as presented in our study can be used for patients with difficulties taken their medication fasted.

Improvement in health-related quality of life (HRQoL) in women with uterine fibroids (Uf) treated with vilaprisan (VPR): a summary of results from asteroid 1 and 2

To assess the impact of VPR, ulipristal acetate (UPA) and placebo on HRQoL in women with UFs. Two multicenter, double-blind, randomized phase 2 studies examining the efficacy and safety of VPR compared with placebo (ASTEROID 1 and 2), and an active comparator (ASTEROID 2). 309 and 172 women with UFs and heavy menstrual bleeding (HMB) were enrolled in ASTEROID 1 and 2, respectively. In ASTEROID 1, women received oral placebo or VPR 0.5 mg, 1 mg, 2 mg, or 4 mg once daily (OD) for 12 weeks, with follow-up at 24 weeks. In ASTEROID 2, women received VPR 2 mg, UPA 5 mg, or placebo OD for one or two 12-week treatment periods, with 12 weeks’ follow-up. HRQoL was assessed using the Uterine Fibroid Symptom and Quality of Life (UFS-QoL) questionnaire and the Short-Form 36 Health Survey Version 2 (SF-36v2) during baseline (BL), end of treatment (EoT) and end of follow-up (EoFUP) visits. Across treatment groups in ASTEROID 1 at BL, the mean (SD) UFS-QoL total HRQoL scores were between 46.2 (24.1) and 49.9 (25.0)SF-36v2 physical component scores (PCS) were between 45.6 (7.3) and 47.5 (7.8), and SF-36v2 mental component scores (MCS) were between 43.3 (11.5) and 47.5 (8.3). All BL scores were in line with previously published data for women with UFs.1 At EoT, the mean total and subscale UFS-QoL and SF-36v2 scores in all VPR-treated groups increased compared with BL. These increases were greater than those observed with placebo. The mean (SD) UFS-QoL total HRQoL scores increased to 83.2 (19.7) in the highest and 78.3 (24.0) in the lowest VPR dose group, versus 56.2 (24.8) in the placebo group. Mean (SD) SF-36v2 PCS and MCS increased to 51.7 (6.2) and 52.0 (8.9) in the lowest VPR dose group, and 53.7 (6.5) and 51.1 (8.9) in the highest VPR dose group, respectively. By comparison, the mean (SD) PCS and MCS at EoT in the placebo group were 48.4 (7.8) and 43.9 (12.2), respectively. The EoT UFS-QoL and SF-36v2 scores of women that received VPR were in the range of those previously published for healthy women without UFs1. Similar results were observed in ASTEROID 2. Mean UFS-QoL HRQoL and SF-36v2 BL scores increased continuously during treatment with VPR for up to 24 weeks, whereas increased scores were observed for the first 12 weeks with UPA but did not continue to 24 weeks (not statistically tested). The mean (SD) UFS-QoL total HRQoL scores across VPR dosage groups increased from between 78.5 (21.0) and 81.9 (16.4) after 12 weeks, to between 82.4 (17.5) and 85.6 (13.2) after 24 weeks’ treatment. In the UPA group, this score decreased from 75.0 (19.6) at 12 weeks to 73.4 (20.8) at 24 weeks. In general, the mean UFS-QoL total HRQoL and SF-36v2 scores decreased only slightly between treatment cessation and EoFUP across active treatment groups in ASTEROID 1 (6 months) and 2 (3 months). In ASTEROID 1 and 2, increases in mean UFS-QoL and SF-36v2 HRQoL scores were observed alongside reduced HMB in women with UFs during active treatment with VPR and UPA for up to 24 weeks, and were sustained to EoFUP. Furthermore, by EoT, HRQoL scores increased to levels previously published for healthy women without UFs.1

Current management of limited-stage SCLC and CONVERT trial impact: Results of the EORTC Lung Cancer Group survey

ObjectivesThe CONVERT trial showed that twice-daily (BD) concurrent chemoradiotherapy should continue to be considered the standard of care in localised LS-SCLC. A survey was conducted to assess the impact of the CONVERT trial in clinical practice and to identify any relevant research questions for future trials in this setting. Methods and materialsAn EORTC Group online survey of LS-SCLC practice was distributed to the EORTC LCG and to members of several European thoracic oncology societies between April and December 2018. Results198 responses were analysed. The majority of respondents (88%, n = 174) were aware of the CONVERT trial. Radiation oncologists comprised 56% of all respondents. Once-daily (OD) radiotherapy is still the most commonly used regimen, however the use of concurrent BD radiotherapy increased after the publication of CONVERT (n = 59/186, 32% prior to and n = 78/187, 42% after the publication, p = 0.053). The main reasons for not implementing BD after the CONVERT publication were logistical issues (n = 88, 44%), inconvenience for patients (n = 56, 28%), and the absence of a statistical survival difference between the two arms in CONVERT (n = 38, 19%). Brain MRI was used by 28% during staging but more than half (60%) of the respondents did not routinely image the brain during follow-up. The main research questions of interest in LS-SCLC were 1) integrating novel targeted therapies-immunotherapies (n = 160, 81%), 2) PCI (+/- hippocampal sparing) vs. MRI surveillance (n = 140, 71%) and, 3) biomarker driven trials (n = 92, 46%). ConclusionOnce daily radiotherapy (60–66 Gy in 30–33 fractions) remains the most prescribed radiotherapy fractionation, despite the findings suggested by the CONVERT trial.

Comparison of Safety, Efficacy, Patient Compliance and Cost-Effectiveness of Transdermal, Oral and Intramuscular Diclofenac for Pain Control Following Oral Surgical Procedures.

To evaluate transdermal diclofenac in terms of analgesic efficacy, safety, compliance and cost-effectiveness and to compare it with oral tablets and intramuscular (IM) injections following surgical removal of impacted mandibular third molars. A prospective, single-centre, multi-arm parallel, randomized study on subjects undergoing extraction of impacted mandibular third molars was conducted between January 2016 and December 2017. The study included 90 participants, 30 in each group. Participants received the standard once daily (OD) dosages of diclofenac in each group for three post-operative days and were advised to consume paracetamol 500mg as rescue analgesics if the pain was not alleviated. Outcome measures such as demographics, duration of surgery, post-operative pain, the number of rescue analgesics taken, adverse drug reactions experienced and overall global assessment for three post-operative days were recorded by the participants on a questionnaire. Transdermal and oral forms achieved similar analgesia on all 3days. Injectable diclofenac had significantly better pain control on the second and third post-operative days compared to tablets and on the third day compared to transdermal diclofenac. A higher number of rescue analgesics was consumed in oral group on day 1. Gastritis and vomiting were seen in 36.66% and 10% cases, respectively, in oral group. 100% of those in IM group had pain on injection. 6.6% complained of dry skin due to patch, while 3.33% had rash and pruritus. Transdermal group had better overall global assessment by patients with 16.67%, 46.67% and 20% participants reporting excellent, very good and good pain control, respectively. The cost in INR was maximum for the transdermal group. Transdermal diclofenac is an excellent alternative to oral and parenteral routes of drug administration in oral surgical procedures with adequate analgesic efficacy, good compliance and fewer side effects.

Abstract CT015: Phase I dose-escalation study of the allosteric AKT inhibitor BAY 1125976 in advanced solid cancer

Abstract This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, was conducted to evaluate the safety, pharmacokinetics, and maximum tolerated dose (MTD) of BAY 1125976 in patients with advanced solid tumors. A dose expansion in hormone receptor (HR) positive metastatic breast cancer (MBC) patients, enriched for patients harboring the AKT1E17K mutation, was included to evaluate the clinical benefit at the recommended Phase II dose (R2D).79 patients (including 39 MBC patients) were enrolled. Mean age was 56.7 years and 61 (77.2%) patients were female. All patients, except one, had received ≥1 prior line of systemic anticancer therapy. Response was measured using RECIST v.1.1.Oral dose escalation was initiated with a continuous once daily (OD) dosing (21 days/cycle), starting with a liquid formulation for the first two dose steps (10 mg and 20 mg OD) and bridging to a tablet formulation for further dose steps (40 mg, 80mg and 120mg OD). Based on toxicity assessment during cycle 1, and additional pharmacokinetic and pharmacodynamic (p-AKT, p-PRAS40 in platelet rich plasma) data, a separate dose escalation using twice daily (BID) dosing tested 40 mg, 60mg and 80mg BID, respectively. The following dose limiting toxicities (DLT) occurred: At 120 mg OD, grade 3 and 4 liver enzyme elevation in two out of 6 patients (2/6) and grade 3 alkaline phosphatase elevation in one patient; at 80mg BID, grade 3 liver enzyme elevation in two out of 4 patients and grade 3 hyperglycemia in one patient. After dose de-escalation according to the continuous reassessment method based study design at 60 mg BID, two out of 6 patients experienced grade 3 liver enzyme elevation. The MTD of BAY 1125976 was determined as 80 mg OD and 60 mg BID, respectively. 28 patients with HR+ MBC were enrolled in the expansion cohort using BAY 1125976 60 mg BID, including nine patients with the AKT1E17K mutation.Pharmacological inhibition of AKT1/2 as shown by inhibition of p-AKT and p-PRAS40 was seen in platelet rich plasma samples. However, among the 78 patients evaluable for response, only 1 (1%) patient with HR+ MBC (AKT1 wild-type) had a partial response (PR), 30 (38%) patients had stable disease (SD) and 38 (49%) patients had progressive disease as best response (data missing from 9 patients). Among 43 patients treated at the R2D, CBR was 27.9%. AKT1E17K mutation status was not associated with tumor response. Molecular characterization of archived tumor samples revealed additional mutations (e.g. PIK3CA, BRCA1/2, KRAS, MYC or FGFR1/2), which may have influenced therapeutic response.In conclusion: Tolerable doses of BAY 1125976 resulted in inhibition of AKT1/2 signaling in platelet rich plasma samples. A notable CBR of 27.9% was achieved at the R2D of BAY 1125976; however PR was seen in only 1 patient with HR+ MBC. Clinical benefit did not correlate with presence of AKT mutations. Citation Format: Andreas Schneeweiss, Dagmer Hess, Markus Joerger, Andrea Varga, Stacy Moulder, Cynthia Ma, Ian Krop, Sara Hurvitz, Christine Rentzsch, Marion Rudolph, Oliver Boix, Gary Wilkinson, Lars Lindbom, Eleni Lagkadinou, Matthias Ocker. Phase I dose-escalation study of the allosteric AKT inhibitor BAY 1125976 in advanced solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT015.

SAT-276 IRON REPLETION IN CKD: A RANDOMIZED TRIAL OF ONCE DAILY VERSUS TWICE DAILY DOSING

Oral iron supplementation, given as divided daily doses, is commonly prescribed in pre-dialysis CKD as iron deficiency and anemia are common. In healthy individuals, the amount of iron absorbed with once daily (OD) dosing has been shown to be as good as with twice daily (BD) dosing despite double cumulative dose with BD dosing. Recently, it has been shown in non-anemic iron deficient young females that elevation in serum hepcidin due to multiple daily doses of oral iron impairs oral iron absorption and that alternate day single dose of oral iron might be preferable.

Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial

BackgroundThe DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. Patients and methodsCediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. ResultsIn case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). ConclusionsThis novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.

1105-P: Impact of Switching from Twice-Daily Basal Insulin (BI) to Once-Daily Insulin Glargine 300 U/mL (Gla-300) in Patients with Type 1 Diabetes (T1DM): Phase 4 Optimize Study

The 28-week, prospective, multicenter, open-label OPTIMIZE study, conducted in Belgium (presented at ADA 2018) and Canada, evaluated treatment optimization with once-daily (OD) Gla-300 in combination with a prandial insulin analog in adults with T1DM previously uncontrolled (HbA1c 8-10%) on twice-daily (BID) BI as part of basal-bolus therapy. The intent-to-treat and safety populations comprised 94 patients (53.2% women; 51.1% from Belgium); mean (SD) age 49.4 (13.1) years and BMI 27.8 (4.7) kg/m². Prior to the study, 45.7% received insulin glargine 100 U/mL and 52.1% insulin detemir. There was a statistically significant reduction in HbA1c from baseline to month 6 (p&amp;lt;0.0001; Table). A statistically significant increase in BI dose (p=0.032) was observed, but there were no significant changes in prandial insulin dose. Hypoglycemic event rates did not significantly change (Table). Statistically significant improvements were seen in the Diabetes Treatment Satisfaction Questionnaire total and perceived hyperglycemia scores, and patient satisfaction score for number of injections (p&amp;lt;0.0001). In this clinically challenging population, better overall treatment satisfaction and improvement in HbA1c, without increase in the rate of hypoglycemia, was achieved on switching from BID to OD Gla-300 plus prandial insulin. Disclosure C. Mathieu: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi. P. Stella: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J. Bruhwyler: Other Relationship; Self; Sanofi. K.C. Alexandre: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. Funding Sanofi (EudraCT 2015-001186-46)

DOACs vs Vitamin K Antagonists: a Comparison of Phase III Clinical Trials and a Prescriber Support Tool.

AIM:The purpose of this article was to systematically review the literature assessing the efficacy and safety of phase III clinical trials for each direct oral anticoagulant versus vitamin K antagonists and to design a “go-to” table for the prescriber.MATERIAL AND METHODS:A systematic review of specialist literature was conducted to identify RCTs which compared direct oral anticoagulants (DOACs) with standard warfarin treatment. Medline, Em-base, and the Cochrane databases were searched from January 2005- January 2019. The inclusion criteria were randomised controlled trials of oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF). Four publications were phase III randomised control trials (RCTs) included in the final analysis.RESULTS:Regarding the primary outcome in RELY the results were 1.69% per 100-year patients (p/y) for Warfarin compared to 1.11% p/y dabigatran etexilate 150mg BD (twice daily). In ROCKET AF the rates of the primary outcome were 2.2% p/y for warfarin compared to 1.7% p/y for rivaroxaban 20 mg OD (once daily). In ARISTOTLE trial the rates of the primary outcome were 1.60% p/y for warfarin compared to 1.27% p/y for apixaban 5 mg BD. In ENGAGE AF TIMI, the rates of the primary outcome were 1.50% p/y for warfarin compared to 1.18% p/y for edoxaban 60mg BD.CONCLUSION:DOACs showed to be either noninferior or superior to warfarin with regards to the primary outcome with better safety patterns. Our “go-to” table provides a supportive tool for physicians in preventing medical errors when managing patients on oral anticoagulants.

Efficacy and safety of once daily versus twice daily mesalazine for mild-to-moderate ulcerative colitis: A meta-analysis of randomized controlled trials.

Background:We aimed to conduct a meta-analysis to evaluate the efficacy and safety between once daily (OD) and twice daily (BD) regime dosing of mesalazine for mild-to-moderate ulcerative colitis (UC).Methods:PubMed, Embase, the Cochrane library, and Web of Science from 1990 to November 2018 were investigated. We searched randomized controlled trials (RCTs) comparing OD with BD regime dosing of mesalazine for mild-to-moderate UC. The software Review Manager 5.3 was used to pool the risk ratio (RR) with a 95% confidence interval (CI).Results:Eight RCTs containing 3495 patients were identified. Regardless of induction of remission or maintenance of remission of UC, OD regime dosing of mesalazine was as effective as BD regime dosing in clinical and endoscopic remission and clinical remission. Also, no obvious difference was found between OD and BD regime dosing of mesalazine regardless of total adverse events, treatment-related adverse events or serious adverse events.Conclusion:OD is as effective and safe as BD regime dosing of mesalazine for active UC.

Safety and efficacy of the human neutrophil elastase inhibitor BAY 85-8501 for the treatment of non-cystic fibrosis bronchiectasis: A randomized controlled trial

BackgroundThere are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Human neutrophil elastase (HNE) is a mediator of tissue destruction in non-CF BE. BAY 85-8501, a selective and reversible HNE inhibitor, could represent a new treatment option for this disease. MethodsThis was a phase 2a, randomized, placebo-controlled, double-blind, parallel-group study. The primary objective was to assess the safety and tolerability of 1 mg BAY 85-8501 once daily (OD) for 28 days compared with placebo in patients with non-CF BE. Secondary objectives were to investigate the effects of 4 weeks of treatment with BAY 85-8501 on health-related quality of life, pulmonary function, and inflammatory and tissue damage biomarkers in sputum, blood and/or urine, and to evaluate the pharmacokinetics of BAY 85-8501. ResultsOverall, 94 patients (mean age, 66 years; 53% male) were randomized (n = 47 per group), and 82 completed the study (BAY 85-8501, n = 37; placebo, n = 45). Treatment-emergent adverse events (TEAEs) occurred in 31 patients (66%) taking BAY 85-8501 and in 36 patients (77%) taking placebo, and were mostly mild or moderate. The serious TEAEs (BAY 85-8501, n = 3; placebo, n = 1) were not considered to be study-drug related.There were no changes in pulmonary function parameters from baseline to end of treatment, and health-related quality of life did not improve in any group. HNE activity in blood after zymosan challenge decreased significantly with BAY 85-8501 treatment (P = 0.0250 versus placebo). There were no significant differences in other biomarkers between treatment groups, with the exception of a small increase in interleukin-8 levels in sputum in the BAY 85-8501 group. Trough plasma concentrations of BAY 85-8501 plateaued after 2 weeks. Conclusions1 mg BAY 85-8501 OD had a favourable safety and tolerability profile when administered for 28 days to patients with non-CF BE. Further studies with a longer treatment duration are needed to evaluate the potential clinical efficacy in this study population.