Flexible Dosing Schedule Research Articles

Suitability and Usefulness of a Flexible Dosing Timing of Oral Semaglutide to Maximize Benefit in Clinical Practice: An Expert Panel.

From clinical trials and observational data, oral semaglutide has proven to be the most effective second-line oral therapy for the management of patients with type 2 diabetes. This review aims to describe the perspective of an Italian expert panel that addressed the potential challenges arising during the use of oral semaglutide in the free-living conditions of routine clinical care. A group of Italian experts discussed and generated insights into the use of oral semaglutide in clinical practice. Key topics included the effectiveness of oral semaglutide in clinical practice, the positioning of the agent to optimize the treatment benefits, the possibility to adopt flexibility in the administration schedule, critical issues encountered, the role of patient communication and information in the importance of dose escalation and management of adverse events. Available data on efficacy and effectiveness of oral semaglutide from randomized clinical trials and real-world studies were reported, along with factors that determine tolerability and persistence on treatment. The debate over a fixed versus a flexible dosing schedule was critically addressed, providing anecdotical clues from a small case series and a real-world database. Additionally, a set of recommendations for clinicians to consider when prescribing oral semaglutide and during the process of patient monitoring were provided.

A first-in-human study of IK-595, an oral MEK/RAF molecular glue, in patients with RAS- or RAF-altered advanced solid tumors.

TPS3185 Background: Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. MEK is a clinically validated cancer target and despite FDA approval of several MEK inhibitors, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas mostly due to early emergence of resistance and low therapeutic indices. IK-595, a potent novel MEK-RAF molecular glue, is being developed to overcome these limitations. IK-595 traps MEK in an inactive complex with all RAF isoforms and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors, in addition to kinase independent CRAF activity. IK-595 exhibits potent single agent activity in a wide range of in vivo cancer models harboring various RAS/RAF alterations, including, but not limited to, lung, pancreatic, colorectal cancer (CRC), melanoma, and AML. The preclinical pharmacokinetic profile of IK-595 also enables flexible dosing schedules resulting in a broader therapeutic window. Methods: This is a phase 1, first-in-human, open-label, multicenter study to evaluate IK-595 as monotherapy in patients with RAS- or RAF-altered advanced solid tumors for whom there are no other further treatment options known to confer clinical benefit. Dose escalation uses a Bayesian Optimal Interval Design (BOIN) in patients with advanced and unresectable, or metastatic solid tumors with confirmed RAS/RAF gene alterations. Backfilling of cleared dose levels with key target indications will initiate upon achievement of efficacious plasma exposures. Dose expansion will occur in genetically defined cohorts, for example NRAS-mutant CRC and malignant melanoma, as well as BRAF non-V600 and KRAS mutant tumors using a Simon 2-stage adaptive design. IK-595 will initially be administered on an intermittent dosing schedule in 30-day cycles. Additional dosing schedules may be explored. Primary objectives of the study are to evaluate safety and tolerability of IK-595 and to determine the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD). Secondary objectives include evaluation of preliminary antitumor activity by RECIST 1.1, pharmacokinetic (PK) parameters, and pharmacodynamic effects of IK-595 on pERK in paired tumor biopsies. Key exploratory endpoints include changes in pERK in peripheral blood cells, changes in pERK target genes in tumor biopsies, and assessment of candidate baseline response biomarkers. The study began in December 2023 and enrollment in Cohort 1 was completed with no DLTs; dose escalation continues to enroll. Clinical trial information: NCT.

Abstract 3296: IK-595, a best-in-class MEK-RAF molecular glue, drives broad and potent anti-tumor activity across RAS-MAPK pathway-altered cancers as a monotherapy and in combination

Abstract Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. Although MEK is a clinically validated cancer target and several MEK inhibitors have been approved by the FDA, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas. We developed the molecular glue, IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 traps MEK in an inactive complex with all RAF isoforms, as well as mutant forms of BRAF (Class I, II, and III), and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that limits the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors. We demonstrate that IK-595 leads to potent and prolonged inhibition of MEK and ERK1/2 phosphorylation in RAS-mutant cancer models. Importantly, IK-595 has a much slower off-rate binding to MEK and retains CRAF longer in an inactive complex with MEK than other MEK/RAF inhibitors, allowing for prolonged target engagement and durable pathway inhibition in RAS/RAF mutant cancer cells. IK-595 exhibits potent single agent activity across a wide range of cancer model indications harboring various RAS/MAPK pathway alterations, including KRAS, NRAS, BRAF and NF1 mutations, and BRAF and CRAF fusions. The benefits of combining IK-595 with inhibitors targeting key resistance mechanisms both within the RAS/MAPK pathway and across parallel survival pathways has also been observed in multiple models. Additionally, IK-595 improved the response of KRAS-driven tumor models to standard of care chemotherapeutic agents, expanding the potential clinical opportunity for IK-595. Key to the design of IK-595 is its PK profile that enables transient high plasma drug exposure and flexible dosing schedules. Intermittent dosing of IK-595 every other day (QOD) or every three days (Q3D) in KRAS-mutant mouse tumor models shows similar efficacy and improved tolerability compared to daily dosing (QD), affording a larger therapeutic window. Preclinical pharmacology studies provide clear guidance to the clinical development plan of IK-595, where flexible dosing schedules, multiple expansion cohorts in RAS/RAF altered patient populations, and combination therapies with mediators of resistance will be explored. IK-595 is a novel MEK-RAF molecular glue that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients with RAS/RAF-driven cancer. Citation Format: Eric Haines, Rachel Catterall, Victor De Jesus, Daniel Hidalgo, Jill Cavanaugh, Marta Sanchez-Martin, Joseph D. Manna, Michael Burke, Bin Li, Sarah R. Wessel, Ao Yang, Sergio Santillana, Jeffrey Ecsedy, X. Michelle Zhang, Sabine K. Ruppel. IK-595, a best-in-class MEK-RAF molecular glue, drives broad and potent anti-tumor activity across RAS-MAPK pathway-altered cancers as a monotherapy and in combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3296.

New evidence for flexible psilocybin dosing in patients with treatment-resistant depression

Psilocybin has demonstrated efficacy for treating depression; however, psychiatrically complex patients have been excluded from trials. A recent clinical trial by Rosenblat at al.1 demonstrates feasibility of a flexible dosing schedule of psilocybin in individuals with severely treatment-resistant depression (TRD), including those with co-morbid conditions or bipolar II disorder (BPII), potentially expanding the current treatment paradigm.

Abstract B155: IK-595, a best-in-class MEK-RAF complex inhibitor, drives broad and potent anti-tumor activity in RAS/RAF-driven tumors

Abstract Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. Although MEK is a clinically validated cancer target and several MEK inhibitors have been approved by the FDA, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas. We developed IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 traps MEK in an inactive complex with all RAF isoforms and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors. We demonstrate that IK-595 leads to potent and prolonged inhibition of MEK and ERK1/2 phosphorylation, in KRAS-mutant cancer and NRAS-mutant melanoma models. In addition to trapping all three RAF isoforms, IK-595 stabilizes the interaction of MEK with BRAF Class I, II, and III mutant proteins. This delays the onset of known resistance mechanisms to other MAPK pathway targeting agents, such as CRAF-mediated pathway reactivation and receptor tyrosine kinase upregulation and/or activation. Importantly, IK-595 has a much slower off-rate binding to MEK and retains CRAF longer in an inactive complex with MEK than other MEK/RAF inhibitors allowing for more prolonged target engagement and durable pathway inhibition in RAS/RAF mutant cancer cells. Moreover, CRAF-ARAF heterodimerization, which is detected in type II pan-RAF inhibitor-treated KRAS mutant cells as an established resistance mechanism, is not observed upon IK-595 treatment. IK-595 exhibits potent signal agent activity across a wide range of cancer models harboring various RAS/RAF alterations, including lung, pancreatic, colorectal cancer (CRC), melanoma, AML, and others. Strong synergy with inhibitors targeting multiple key mechanisms, both within the RAS/MAPK pathway and across parallel survival pathways, has also been observed in multiple models. Key to the design of IK-595 is its PK profile that enables transient high plasma drug exposure and flexible dosing schedules. Intermittent dosing of IK-595 every other day (QOD) or every three days (Q3D) in KRAS mutant mouse tumor models shows similar efficacy and improved tolerability compared to daily dosing (QD), affording a larger therapeutic window. Preclinical pharmacology studies provide clear guidance to the clinical development plan of IK-595, where flexible dosing schedules and multiple expansion cohorts in RAS/RAF altered patient populations will be explored. IK-595 is a novel MEK-RAF complex inhibitor that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients with RAS/RAF-driven cancer. Citation Format: Eric Haines, Rachel Catterall, Victor De Jesus, Bin Li, Sarah R Wessel, Jill Cavanaugh, Michael Burke, Joseph D Manna, Okzana Zavidij, Ao Yang, Lan Xu, Sergio Santillana, Jeffrey Ecsedy, X. Michelle Zhang, Sabine K Ruppel. IK-595, a best-in-class MEK-RAF complex inhibitor, drives broad and potent anti-tumor activity in RAS/RAF-driven tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B155.

Insulin Glargine 300 U/mL Therapy in Children and Adolescents with Type 1 Diabetes.

The pharmacokinetic and pharmacodynamic properties of the second-generation basal insulin glargine 300 Units/mL (Gla-300) may be of benefit in the treatment of type 1 diabetes mellitus (T1DM). Gla-300 provides a stable and sustained time-action profile, which is associated with glycaemic control and flexible dosing schedule. This review summarises the available evidence on the safety and efficacy of Gla-300 in children and adolescents with T1DM. Gla-300 is as effective as the first-generation basal insulin glargine 100 Units/mL (Gla-100), a standard of care for patients with diabetes in reducing HbA1c, and shows a lower risk of severe hypoglycaemia and hyperglycaemia in children and adolescents with T1DM. However, Gla-300 and Gla-100 are not bioequivalent and are not directly interchangeable. Real-world studies on patients aged 6–17 years are limited. To date, only one small study assessed the effectiveness and safety of Gla-300 versus Gla-100 in newly diagnosed T1DM paediatric patients, confirming the treatment safety and effectiveness of Gla-300 in clinical practice. Gla-300 is a longer-acting basal insulin alternative in the management of children (aged ≥ 6 years) and adolescents with T1DM.

Extended-release buprenorphine outcomes among treatment resistant veterans

ABSTRACT Background: Buprenorphine Extended-Release (BUP-XR) is an FDA approved, monthly subcutaneous injection for opioid use disorder. This formulation provides an alternative for patients who have difficulty adhering to daily sublingual buprenorphine; however, its cost may be prohibitive compared to other medication alternatives. Objectives: The objective of this project was to evaluate the effectiveness of BUP-XR and provide a rationale for its utilization in health care facilitates. Methods: Across two VA outpatient clinics, twenty-six (22 male, 4 female) clinically complex patients received at least one BUP-XR injection between December 1, 2018 and April 1, 2020. The sample was high risk for hospital admission and mortality. Data was collected retrospectively from the medical records. Outcomes examined included: medication adherence, urine drug and alcohol screenings, emergency department visits, hospital admissions, and housing status. Within-subject comparisons were made between the six month period prior to and following the first injection. Results: Treatment retention was robust, as 81% of the sample received six or more monthly BUP-XR injections. Most patients (77%) maintained 300 mg dosage and a majority (70%) missed or were late for at least one injection. BUP-XR was associated with reduction in: emergency department visits, days of hospitalization, non-prescribed opioid use, and homelessness. Mortality rate was 23%. Conclusions: BUP-XR with a flexible dosing schedule and a nonstandard default dose of 300 mgs resulted in robust retention, provided effective treatment of OUD, and reduced health care utilization for these complex patients with high mortality risk. However, due to the lack of statistical significance generalization of these findings is limited.

Serum vibriocidal responses when second doses of oral cholera vaccine are delayed 6 months in Zambia

Two-dose killed oral cholera vaccines (OCV) are currently being used widely to control cholera. The standard dose-interval for OCV is 2 weeks; however, during emergency use of the vaccine, it may be more appropriate to use the available doses to quickly give a single dose to more people and give a delayed second dose when more vaccine becomes available.This study is an open label, randomized, phase 2 clinical trial of the vibriocidal response induced by OCV, comparing the responses when the second dose was given either 2 weeks (standard dose interval) or 6 months (extended dose interval) after the first dose. Vaccine was administered to healthy participants > 1 year of age living in the Lukanga Swamps area of Zambia. Three age cohorts (<5 years, 5–14 years, and ≥ 15 years) were randomized to the either dose-interval. The primary outcome was the vibriocidal GMT 14 days after the second dose.156 of 172 subjects enrolled in the study were included in this analysis. The Inaba vibriocidal titers were not significantly different 14 days post dose two for a standard dose-interval GMT: 45.6 (32–64.9), as compared to the GMT 47.6 (32.6–69.3), for the extended dose-interval, (p = 0.87). However, the Ogawa vibriocidal GMTs were significantly higher 14 days post dose two for the extended-dose interval at 87.6 (58.9–130.4) compared to the standard dose-interval group at 49.7 (34.1–72.3), p = 0.04. Vibriocidal seroconversion rates (a > 4-fold rise in vibriocidal titer) were not significantly different between dose-interval groups.This study demonstrated that vibriocidal titers 14 days after a second dose when given at an extended\\ dose interval were similar to the standard dose-interval. The findings suggest that a flexible dosing schedule may be considered when epidemiologically appropriate.The trial was registered at Clinical Trials.gov (NCT03373669).

Abstract 1724: Microinjection of Nectin-4/CD137 tumor-targeted immune cell agonist (TICA™) activates the local tumor microenvironment

Abstract A new generation of both systemic and targeted CD137 agonists are entering clinical development following agonistic anti-CD137 (4-1BB) antibody development nearly a decade ago. However, each of these molecules rely on biologic agents with potentially suboptimal properties for CD137 agonism due to their relatively large size and long circulating half-lives which may limit their tissue penetration, cause sustained agonism resulting in overstimulation and activation-induced lymphocyte cell death. Fully synthetic constrained bicyclic peptides (Bicycles™) with antibody-like affinities and target selectivity are uniquely suited to circumvent limitations of other targeted CD137 agonistic therapeutics. BT7480 and BCY11864 are tumor targeted immune cell agonists (TICA) designed to deliver a highly potent CD137 agonist to Nectin-4 overexpressing tumors with a flexible dosing schedule maximizing anti-tumor activity while circumventing the need for continuous systemic exposure. The Comparative In Vivo Oncology (CIVO) platform has been developed to enable in situ investigation of multiple microdosed drugs simultaneously in human tumors with safety and feasibility of this platform recently demonstrated in patients with soft tissue sarcomas. CIVO percutaneously injects drug microdoses directly into tumor tissue as trackable columns where tissue can be analyzed after resection for the effect of the drug treatment in the tumor. Here we report on an evaluation of the feasibility of using the CIVO -platform to demonstrate the mechanism of action of our tumor target-dependent CD137 agonist TICAs. Both BT7480 and BCY11864 demonstrate extremely potent Nectin-4-dependent CD137 agonism in primary human PBMC/tumor cell co-culture assays. Systemic administration of BT7480 in Nectin-4 expressing tumors in immunocompetent mice leads to profound reprogramming of the tumor immune microenvironment including a rapid increase in T cell chemotactic cytokine transcripts and macrophage gene signatures followed by an increase in cytotoxic cell gene signature and increase in intratumoral CD8+ T cells. CIVO was used to demonstrate the in vivo mechanism of action of a Nectin-4/CD137 TICA. Micro-injection of BCY11864 into Nectin-4 expressing tumors in immunocompetent mice led to dose dependent induction of immune activation markers in the tumor microenvironment and activation of the tumor resident cytotoxic T cells was evident 24 hours after BCY11864 micro-injection. Akin to our findings with transcriptional profiling of the tumor response to BT7480, BCY11864 activity was shown not to be limited to T cells but also included other CD137 positive cell populations such as myeloid and NK cells. We hypothesize that tumor targeted CD137 agonism may lead to initial myeloid cell response that enhances the cytotoxic T cell recruitment and activation in the tumor tissue. Citation Format: Johanna Lahdenranta, Stephen J. Blakemore, Kristen Hurov, Marc O. Grenley, Punit Upadhyaya, Carly Campbell, Elizabeth Repash, Eric Haines, Philip E. Brandish, Richard A. Klinghoffer, Nicholas Keen. Microinjection of Nectin-4/CD137 tumor-targeted immune cell agonist (TICA™) activates the local tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1724.

Challenges in conducting paediatric trials with off-patent drugs

IntroductionFor more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge. AimThis paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement. DiscussionOff-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug. ConclusionFacilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life.

Meningococcal-group B (MenB) vaccine series completion and adherence to dosing schedule in the United States: A retrospective analysis by vaccine and payer type

BackgroundTwo MenB vaccines with different dosing schedules are approved in the US: MenB-4C (2 doses) and MenB-FHbp (2–3 doses). Both vaccines were licensed on the basis of immunogenicity demonstrated after vaccine series completion. We evaluated vaccination completion and adherence to dosing schedules. MethodsThis retrospective analysis used data from MarketScan Commercial Claims and Encounters Database (Commercial) January 1, 2015 - February 28, 2018 and Multi-State Medicaid Database (Medicaid) January 1, 2015 - December 31, 2017 to examine vaccine series completion and adherence to dosing schedule in individuals who initiated a MenB series at ages 16–23 years. Vaccine series completion and dose schedule adherence were assessed during a 15-month follow-up period after the first dose. Completion was defined as individual receipt of the recommended number of doses, with current recommendations applied retroactively to allow individuals who initiated the MenB-FHbp series to be complete with either the 2- or the 3-dose schedule. ResultsThe study population comprised 65,205 commercially-insured individuals (36,118 initiated MenB-4C; 29,087 initiated MenB-FHbp) and 13,535 Medicaid-covered individuals (10,153 initiated MenB-4C; 3382 initiated MenB-FHbp). In Commercial, 63% of individuals who initiated MenB-4C and 52% of individuals who initiated MenB-FHbp completed vaccination within 15 months; dosing schedule adherence was 62% for MenB-4C initiators and 18% for MenB-FHbp initiators. In Medicaid, 15-month completion rates for MenB-4C and MenB-FHbp initiators were 49% and 31%, respectively, with corresponding dosing schedule adherence of 48% and 8%. Among individuals who completed the series, median time to completion was 68 days for MenB-4C versus 258 days for MenB-FHbp in Commercial and 88 days for MenB-4C versus 309 days for MenB-FHbp in Medicaid. ConclusionDuring the study period, MenB vaccine series completion was suboptimal. However, completion was significantly higher for MenB-4C, with notably shorter time to completion. This may reflect the flexible dosing schedule of MenB-4C.

Safety and Efficacy of Repeat Administration of Triamcinolone Acetonide Extended-release in Osteoarthritis of the Knee: A Phase 3b, Open-label Study.

IntroductionThe aim of this work is to assess the safety and efficacy of repeat administration of triamcinolone acetonide extended-release (TA–ER) in patients with symptomatic knee osteoarthritis (OA), including those with advanced radiographic severity.MethodsIn this phase 3b, single-arm, open-label study, patients aged ≥ 40 years received the first intra-articular TA-ER injection on day 1. Patients received the second injection timed to the response to the first injection (at either week 12, 16, 20, or 24). Patients who received two injections were evaluated every 4 weeks for 52 weeks. Safety was evaluated via treatment-emergent adverse events and any change at 52 weeks in index-knee radiographs (chondrolysis, osteonecrosis, insufficiency fractures, subchondral bone changes). Exploratory efficacy endpoints included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A (pain), -B (stiffness), -C (function), and Knee Injury and Osteoarthritis Outcome Score-Quality of Life (KOOS-QoL) after each injection. Initiative in Methods, Measurements and Pain Assessment in Clinical Trials (IMMPACT) criteria were used to determine moderate and substantial treatment response.ResultsA total of 208 patients were enrolled and received the first injection of TA-ER; 179 (86.1%) received the second injection (median time to second injection: 16.6 weeks). Both injections were well tolerated, with no unexpected adverse events or significant radiographic changes at week 52. The magnitude and duration of clinical benefit after the first and second injections were similar, and most patients reported a substantial (≥ 50%) analgesic response after both doses.ConclusionsRepeat administration of TA–ER using a flexible dosing schedule timed to patient response was well tolerated, with no radiographic evidence of cartilage impact. Both injections resulted in similar improvements in OA symptoms across a broad spectrum of disease severity reflective of that seen in clinical practice.Trial Registration InformationClinicalTrials.gov identifier: NCT03046446.FundingFlexion Therapeutics, Inc.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s40744-019-0140-z) contains supplementary material, which is available to authorized users.

The OPTIMA study, buprenorphine/naloxone and methadone models of care for the treatment of prescription opioid use disorder: Study design and rationale

BackgroundRates of non-medical use of opioids, and opioid use disorders (OUD) have been rising throughout North America. Methadone and buprenorphine/naloxone are the recommended first-line treatment options for OUD in Canada. Most studies to date have been conducted among heroin users, in controlled settings, and using similar strict dosing schedules (i.e., daily witnessed ingestion) despite buprenorphine/naloxone's superior safety profile, which allows a more flexible take-home dosing schedule. This study was designed to assess the relative effectiveness of buprenorphine/naloxone- and methadone-based models of opioid agonist therapy (OAT) for the treatment of prescription opioid use disorder (POUD) in routine clinical care. MethodsOPTIMA is a multicenter, open-label, pragmatic, randomized, two-arm, non-inferiority, 24-week study comparing the relative effectiveness of buprenorphine/naloxone (provided via flexible take-home doses) to methadone (provided via daily witnessed ingestion) models of OAT for the treatment of POUD. Approximately 276 non-pregnant adults meeting DSM-5 criteria for OUD, currently not in OAT, will be randomized across 7 Canadian sites. The primary outcome is reduction of non-medical opioid use, measured by bi-weekly urine drug screens during the 24-week study period. Secondary outcomes include treatment retention and satisfaction, safety, medication adherence, and patient engagement. DiscussionThe OPTIMA study is the first randomized clinical trial to compare the relative effectiveness of buprenorphine/naloxone (flexible take-home doses) versus methadone (daily witnessed ingestion) models of OAT for POUD in real-world clinical settings. This study will generate urgently needed evidence towards treatment options to guide the health system response to the ongoing opioid crisis. Clinical trial registrationNCT03033732.

An Adjustable Dalteparin Sodium Dose Regimen for the Prevention of Clotting in the Extracorporeal Circuit in Hemodialysis: A Clinical Trial of Safety and Efficacy (the PARROT Study).

Background:Dalteparin sodium, a low-molecular-weight heparin, is indicated for prevention of clotting in the extracorporeal circuit during hemodialysis (HD). Product labeling recommends a fixed single-bolus dose of 5000 international units (IU) for HD sessions lasting up to 4 hours, but adjustable dosing may be beneficial in clinical practice.Objective:The aim of the PARROT study was to investigate the safety and efficacy of an adjustable dose of dalteparin in patients with end-stage renal disease requiring 3 to 4 HD sessions per week.Design:A 7-week, open-label, multicenter study with a single treatment arm, conducted between October 2013 and March 2016.Setting:Ten sites in Canada.Patients:A total of 152 patients with end-stage renal disease requiring 3 to 4 HD sessions per week.Measurements:The primary outcome was the proportion of HD sessions completed without premature termination due to inadequate anticoagulation.Methods:All participants initially received a dose of 5000 IU dalteparin, which could be adjusted at subsequent HD sessions when clinically indicated, by increment or decrement of 500 or 1000 IU, with no specified dose limits.Results:Patients were followed for 256 patient-months. Nearly all (99.9%; 95% confidence interval [CI]: 99.7-100) evaluable HD sessions were completed without premature clotting. Dose was adjusted for more than half (52.3%) of participants, mostly owing to clotting or access compression time >10 minutes. Median dalteparin dose was 5000 IU (range: 500-13 000 IU). There were no major bleeds, and minor bleeding was reported in 2.3% of all HD sessions. There was no evidence of bioaccumulation.Limitations:This short-term study, with a single treatment arm, was designed to optimize dalteparin dose using a flexible dosing schedule; it was not designed to specifically evaluate dalteparin dose minimization, provide a direct comparison of dalteparin versus unfractionated heparin, or provide information on long-term safety for flexible dalteparin dosing. Patients were excluded if they were at high risk of bleeding, including those on anticoagulants and those on antiplatelet agents other than aspirin <100 mg/d.Conclusions:Overall, an adjustable dalteparin sodium dose regimen allowed safe completion of HD, with clinical benefits over fixed dosing.Trial Registration:ClinicalTrials.gov NCT01879618, registered June 13, 2013.

Repetitive Transcranial Magnetic Stimulation (5 and 10 Hz) With Modified Parameters in the Treatment of Resistant Unipolar and Bipolar Depression in a Private Practice Setting.

A limited number of studies have investigated the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of resistant depression in an outpatient private practice setting. We hypothesized that rTMS would be safe and effective in the treatment of resistant depression in a nonresearch population. We treated 22 outpatients with unipolar or bipolar depression who were experiencing a moderate to severe treatment-resistant major depressive episode (MDE). Treatment was based on a flexible dose schedule of either 5 Hz or 10 Hz rTMS applied over the left dorsolateral prefrontal cortex with modified parameters. Assessments were performed at baseline, then on a weekly basis. The patients had received at least 2 trials of antidepressant medication of an adequate dose and duration without satisfactory improvement in the index MDE. There was a significant change in Montgomery-Asberg Depression Rating Scale scores from baseline (29.14±5.85) to the end of week 4 (16.27±11.20); 50.00% (11/22) were responders and 40.9% (9/22) achieved remission. No major side effects were observed aside from mild headache in some patients. rTMS applied to the left dorsolateral prefrontal cortex was safe and effective in an important subset of outpatients with a moderate to severe MDE in a naturalistic setting. Outcomes demonstrated response rates similar to research populations. Further larger studies are needed to confirm the safety and effectiveness of rTMS in naturalistic conditions.

Photosensitizer-eluting nanofibers for enhanced photodynamic therapy of wounds: A preclinical study in immunocompromized rats

Electrospun nanofibers (NFs) as drug delivery/tissue regeneration template and antimicrobial photodynamic therapy (APDT) have been widely investigated as two different approaches to enhance wound healing. In the present study, the two approaches were combined in a single platform for greater healing enhancement potentials. Composite photosensitizer-eluting NFs were developed using a polyhydrohybutyrate/polyethylene glycol (60:40 PHB/PEG) polymer blend and methylene blue (MB) as antimicrobial photosensitizer (PS). NFs protected the photoactivity of entrapped MB, enhanced its photodynamic activity against two wound bacteria, Staphylococcus aureus standard strain (SAst) and MRSA and sustained MB release allowing for flexible PS dosing and irradiation schedules. This combined PS-eluting NFs/APDT approach proved effective in the treatment of SAst-inoculated excision wounds in a challenging immunocompromized rat model. This was verified by morphological, morphometric, microbiological, histopathological and RT-PCR studies. Inclusion of PS-eluting NFs as an additional active component of APDT generates a combined non-antibiotic antimicrobial/cell regeneration approach with great potentials for wound healing and other biomedical applications.

Insulin degludec in a simple or stepwise titration algorithm in a Japanese population of patients with type 2 diabetes: a randomized, 26-week, treat-to-target trial.

Managing insulin therapy is a challenge for both patients and healthcare providers.The primary aim of this trial was to compare the efficacy and safety of insulin degludec (IDeg) in a fixed versus flexible dosing schedule. The secondary aim and subject of this manuscript was to compare a simple versus a stepwise titration algorithm. This was a 26-week, controlled, multicenter, open-label, randomized, treat-to-target phase 3b trial of Japanese patients with type 2 diabetes inadequately treated with insulin glargine and with/without antidiabetic drugs orally. The trial had a 2×2 factorial design whereby 458 patients were randomized 1:1:1:1 to one of two titration algorithms and one of two dosing schedules. IDeg dose was adjusted weekly using a clinician-led, treat-to-target approach in order to ensure optimal insulin titration and glycemic control following self-measured blood glucose (SMBG) readings. Mean insulin dose at the end of the trial was similar in both simple and stepwise titration algorithms. Glycemic control improved in both titration algorithms, with noninferiority in glycated hemoglobin (HbA1c) reduction confirmed when comparing simple and stepwise titration algorithms and no significant differences in fasting plasma glucose or SMBG at 26weeks. No safety concerns were observed in terms of adverse events, and rates of hypoglycemia were not significantly different between the two algorithms. This trial demonstrated comparable efficacy with noninferior HbA1c and comparable safety of once-daily IDeg using either a simple or stepwise titration algorithm in Japanese patients with type 2 diabetes inadequately controlled with insulin glargine.

4SC-202: Epigenetic modulation to pave the way for checkpoint inhibition.

11546 Background: 4SC-202 is an orally available, small molecule clinical stage epigenetic modulator. Epigenetic modifiers are known to bear the potency to enhance response rates of checkpoint inhibitors and broaden the number of indications by combination treatment. Methods: 4SC-202 was tested in cellular assays and in a syngenic mouse model to investigate its capacity for immune modulation and combination treatment with checkpoint inhibitors. Results: Preclinical data demonstrate that 4SC-202 has immune priming potency by up-regulation of i) tumor associated antigens, ii) ligands for NK cell recognition, iii) MHC and costimulatory molecules, and iv) down-regulation of immunosuppression via the suppression of IDO and arginase in tumor cells as well as in myeloid-derived suppressor cells. In contrast to Entinostat and SAHA, 4SC-202 is not toxic for immune cells. By sparing the immune cells and enhancing the immunogenicity of tumor cells, 4SC-202 enables the immune system to attack tumor cells and provides a rationale for the combination with checkpoint inhibitors. To translate these effects from in vitro to in vivo, 4SC-202 was tested in a syngenic colon carcinoma CT26 mouse model in monotherapy and in combination with anti-PD1 antibody. 4SC-202 inhibited the growth of CT26 tumors at clinically relevant doses and therefore confirmed the relevance of the immunomodulating capacity of 4SC-202 for the anti-tumoral effect. The combination treatment with anti-PD1 antibody demonstrated that 4SC-202 is able to sensitize tumors for treatment with checkpoint inhibitors in indications where checkpoint inhibitors alone are not active. Conclusions: As demonstrated in a phase I clinical trial in 24 patients with relapsed or refractory hematological malignancies, 4SC-202 was well tolerated and objective responses (1 CR, 1 PR) and disease stabilizations were observed in several patients. 4SC-202 is an ideal combination partner for checkpoint inhibitors due to its immune priming capacity, the excellent safety profile and the oral formulation which allows convenient application and flexible dosing schedules.

Clinical Review of Shanchol™ (a WHO pre-qualified oral cholera vaccine)

Background: Cholera caused by Vibrio cholerae of the O1 or O139 serogroup is an important cause of severe dehydrating diarrhea in adults and children. It continues to be a major global health problem. The WHO estimates that 3-5 million cases and 100,000–130,000 deaths occur per year globally, predominantly in Asia and Africa. The WHO recommends that in cholera-endemic countries, vaccination should be used as an additional tool to control cholera along with longer term interventions of improving water and sanitation. It recommends pre-emptive vaccination to help prevent potential outbreaks or the spread of current outbreaks. Shanchol™ is a ready-to-use killed bivalent (O1 and O139) whole-cell oral cholera vaccine administered as 2 doses 14 days apart in individuals aged 1 year and above. There is no need for buffer or water for its administration. It is currently licensed in India and 17 other countries in Asia, Africa and Latin America. It is prequalified for international use by the WHO. The vaccine is the basis for the WHO stockpile which is used to help control cholera epidemics. Methods & Materials: Clinical analysis of safety, immunogenicity and efficacy studies of Shanchol™ Results: Overall, ∼66,000 doses have been administered to subjects during the clinical development of the vaccine. Shanchol™ was observed to provide sustained protective efficacy level of 65% for at least 5 years in a clinical trial conducted in over 69,000 subjects in India. The herd effect conferred by Shanchol™ was evident with minimum vaccine coverage of 38% and was sustained for at least 3 years. Safety and immunogenicity clinical trials conducted in India, Bangladesh, Ethiopia, Philippines and Haiti showed that the vaccine is safe and provides good immune responses in different endemic populations. Results from a clinical study showed that flexible dosing schedule of Shanchol™ as 2 doses 14 to 28 days apart is possible. A modeling study observed that single-dose vaccination may prevent more deaths during outbreaks than 2-dose vaccination. Shanchol™ was also observed to be highly effective in mass vaccination campaigns in Guinea, Haiti, Odisha (India) and Bangladesh. Conclusion: Shanchol™ vaccine is safe and effective for control of cholera in endemic countries

A review of the efficacy and safety of mirodenafil in the management of erectile dysfunction.

Erectile dysfunction (ED) is a common disorder that can jeopardize quality of life and the partnership of patients and their sexual partners. The advent of oral phosphodiesterase type 5 inhibitors (PDE5Is) has revolutionized a treatment for ED, and they are recognized as the first-line therapy for ED, regardless of its etiology. Mirodenafil, a second-generation PDE5I, has biochemical profiles such as high affinity for PDE5 and high selectivity for PDE5 over other PDE isoforms, compared to other existing PDE5Is such as sildenafil, vardenafil and tadalafil. Available evidence has suggested that doses of 50 and 100 mg mirodenafil effectively improve ED [with improvements in the erectile function domain of the International Index of Erectile Function (IIEF-EF) scores, positive responses to questions 2 of the Sexual Encounter Profiles (SEP2) and questions 3 of the Sexual Encounter Profiles (SEP3): 7.6-11.6 points, 27.72-38.98% and 44.20-67.33%, respectively] in a broad range of patient populations with ED of a variety of underlying etiologies, severities and ages, without any serious treatment-related adverse effects. In the treatment of diabetic ED, a traditionally difficult-to-treat population, 100 mg mirodenafil has been reported to offer favorable efficacy (with improvements in the IIEF-EF scores, and positive responses to the SEP2 and the SEP3: 9.3 points, 36.1% and 61.8%, respectively) and tolerability (mild adverse effects of less than 19.6%), which are comparable with results from clinical studies on other PDE5Is. Mirodenafil appears to be effective, safe and well tolerated in men with both ED and hypertension or lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) who are taking concomitant antihypertensive medications or α1-blockers. Furthermore, recent evidence has indicated that mirodenafil may be a potential option for chronic dosing in the treatment of ED despite its short half-life (T 1/2). Most of the available clinical studies have reported that adverse effects (up to 53.7%) caused by 50 and 100 mg mirodenafil are mild or moderate in severity, with headache (1.8-14.8%) and flushing (6.7-24.1%) being the most common. Due to the pharmacodynamic profiles of mirodenafil, its tolerability is expected to be somewhat better than those of the other PDE5Is. However, further well designed studies with larger cohorts of different ethnicities, flexible dosing schedules and long-term follow up are necessary to confirm the favorable efficacy and tolerability profiles of mirodenafil for the treatment of ED.