A phase II study of guadecitabine combined with irinotecan vs regorafenib or TAS-102 in irinotecan-refractory metastatic colorectal cancer patients.

DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle. Between January 15, 2016 and October 24, 2018, 104 pts were randomized at four international sites, with 96 pts undergoing treatment, 62 in Arm A and 34 in Arm B. Median overall survival was 7.15 months for Arm A and 7.66 months for Arm B (HR 0.93, 95% CI: 0.58-1.47, P = .75). The Kaplan-Meier rates of progression free survival at 4 months were 32% in Arm A and 26% in Arm B. Common ≥Grade 3 treatment related adverse events in Arm A were neutropenia (42%), anemia (18%), diarrhea (11%), compared to Arm B pts with neutropenia (12%), anemia (12%). Guadecitabine and irinotecan had similar OS compared to standard of care TAS-102 or regorafenib, with evidence of target modulation. Clinical trial information: NCT01896856.

Exploratory comparative transcriptomic analysis reveals potential gene targets associated with Cry1A.105 and Cry2Ab2 resistance in fall armyworm (Spodoptera frugiperda).

Genetically modified (GM) crops, expressing Bacillus thuringiensis (Bt) insecticidal toxins, have substantially transformed agriculture. Despite rapid adoption, their environmental and economic benefits face scrutiny due to unsustainable agricultural practices and the emergence of resistant pests like Spodoptera frugiperda, known as the fall armyworm (FAW). FAW's adaptation to Bt technology in corn and cotton compromises the long-term efficacy of Bt crops. To advance the understanding of the genetic foundations of resistance mechanisms, we conducted an exploratory comparative transcriptomic analysis of two divergent FAW populations. One population exhibited practical resistance to the Bt insecticidal proteins Cry1A.105 and Cry2Ab2, expressed in the genetically engineered MON-89Ø34 - 3 maize, while the other population remained susceptible to these proteins. Differential expression analysis supported that Cry1A.105 and Cry2Ab2 significantly affect the FAW physiology. A total of 247 and 254 differentially expressed genes were identified in the Cry-resistant and susceptible populations, respectively. By integrating our findings with established literature and databases, we underscored 53 gene targets potentially involved in FAW's resistance to Cry1A.105 and Cry2Ab2. In particular, we considered and discussed the potential roles of the differentially expressed genes encoding ABC transporters, G protein-coupled receptors, the P450 enzymatic system, and other Bt-related detoxification genes. Based on these findings, we emphasize the importance of exploratory transcriptomic analyses to uncover potential gene targets involved with Bt insecticidal proteins resistance, and to support the advantages of GM crops in the face of emerging challenges.

Nab-paclitaxel plus S-1 followed by gemcitabine-oxaliplatin as first-line alternating sequential treatment of pancreatic ductal adenocarcinoma.

BACKGROUND: Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC). METHODS: This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125 mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60 mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130 mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes. RESULTS: Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months. CONCLUSION: The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867).

Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis.

OBJECTIVE: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy. METHODS: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment. RESULTS: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis. CONCLUSIONS: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT05540275.

SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer.

BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC). METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II). RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC. CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

Bayesian sample size determination in basket trials borrowing information between subsets.

Basket trials are increasingly used for the simultaneous evaluation of a new treatment in various patient subgroups under one overarching protocol. We propose a Bayesian approach to sample size determination in basket trials that permit borrowing of information between commensurate subsets. Specifically, we consider a randomized basket trial design where patients are randomly assigned to the new treatment or control within each trial subset ("subtrial" for short). Closed-form sample size formulae are derived to ensure that each subtrial has a specified chance of correctly deciding whether the new treatment is superior to or not better than the control by some clinically relevant difference. Given prespecified levels of pairwise (in)commensurability, the subtrial sample sizes are solved simultaneously. The proposed Bayesian approach resembles the frequentist formulation of the problem in yielding comparable sample sizes for circumstances of no borrowing. When borrowing is enabled between commensurate subtrials, a considerably smaller trial sample size is required compared to the widely implemented approach of no borrowing. We illustrate the use of our sample size formulae with two examples based on real basket trials. A comprehensive simulation study further shows that the proposed methodology can maintain the true positive and false positive rates at desired levels.

Efficacy and Safety of TAS-303 in Female Patients With Stress Urinary Incontinence: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). MATERIALS AND METHODS: A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. RESULTS: In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. CONCLUSIONS: Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).

iCare - a self-directed, interactive online program to improve health and wellbeing for people living with upper gastrointestinal or hepato-pancreato-biliary cancers, and their informal carers: the study protocol for a Phase II randomised controlled trial.

BACKGROUND: Up to 70% of people diagnosed with upper gastrointestinal (GI) tract or hepato-pancreato-biliary (HPB) cancers experience substantial reductions in quality of life (QoL), including high distress levels, pain, fatigue, sleep disturbances, weight loss and difficulty swallowing. With few advocacy groups and support systems for adults with upper GI or HPB cancers (i.e. pancreas, liver, stomach, bile duct and oesophageal) and their carers, online supportive care programs may represent an alternate cost-effective mechanism to support this patient group and carers. iCare is a self-directed, interactive, online program that provides information, resources, and psychological packages to patients and their carers from the treatment phase of their condition. The inception and development of iCare has been driven by consumers, advocacy groups, government and health professionals. The aims of this study are to determine the feasibility and acceptability of iCare, examine preliminary efficacy on health-related QoL and carer burden at 3- and 6-months post enrolment, and the potential cost-effectiveness of iCare, from health and societal perspectives, for both patients and carers. METHODS AND ANALYSIS: A Phase II randomised controlled trial. Overall, 162 people with newly diagnosed upper GI or HPB cancers and 162 carers will be recruited via the Upper GI Cancer Registry, online advertisements, or hospital clinics. Patients and carers will be randomly allocated (1:1) to the iCare program or usual care. Participant assessments will be at enrolment, 3- and 6-months later. The primary outcomes are i) feasibility, measured by eligibility, recruitment, response and attrition rates, and ii) acceptability, measured by engagement with iCare (frequency of logins, time spent using iCare, and use of features over the intervention period). Secondary outcomes are patient changes in QoL and unmet needs, and carer burden, unmet needs and QoL. Linear mixed models will be fitted to obtain preliminary estimates of efficacy and variability for secondary outcomes. The economic analysis will include a cost-consequences analysis where all outcomes will be compared with costs. DISCUSSION: iCare provides a potential model of supportive care to improve QoL, unmet needs and burden of disease among people living with upper GI or HPB cancers and their carers. AUSTRALIAN AND NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12623001185651. This protocol reflects Version #1 26 April 2023.

A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial.

BACKGROUND: Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM. METHODS: ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events. DISCUSSION: Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development. TRIAL REGISTRATION: ISRCTN: 11460478. CLINICALTRIALS: Gov: NCT05629702.

Methods Article for a Study Protocol: Study Design and Baseline Characteristics for Aldosterone Synthase Inhibition in Chronic Kidney Disease.

INTRODUCTION: Aldosterone synthase (AS) inhibition may overcome increased aldosterone production in response to renin-angiotensin system inhibition. BI 690517 is an AS inhibitor under investigation for chronic kidney disease (CKD). METHODS: This multinational, phase II, double-blind study (NCT05182840) investigated the efficacy and safety of daily oral BI 690517, with or without empagliflozin 10 mg, in participants with CKD. The primary endpoint was change from baseline in urine albumin:creatinine ratio (UACR) at week 14. Between February 18, 2022, and December 30, 2022, 714 adults already treated by angiotensin-converting enzyme inhibitor (30.5%) or angiotensin receptor blocker (69.8%) were randomized (1:1) to an 8-week run-in to assign background empagliflozin (n = 356) or placebo (n = 358). Participants in each group were then randomized (1:1:1:1) to a 14-week treatment period with BI 690517 (3 mg, 10 mg, or 20 mg) or placebo. Of the 714 participants who entered run-in, 586 were randomized to the treatment period. They were predominantly men (66.6%) of white race (58.4%) with a mean (standard deviation [SD]) age of 63.8 (11.3) years. Type 2 diabetes was present in 414 participants (70.6%). The baseline mean (SD) estimated glomerular filtration rate was 51.9 (17.7) mL/min/1.73 m2, and median (interquartile range) UACR was 426.3 mg/g (205.3-888.5). CONCLUSION: This study will inform dose selection for further clinical development and determine whether BI 690517, with or without background empagliflozin, has a favorable safety profile and potential for additive kidney protection in participants with CKD already treated with a renin-angiotensin system inhibitor.

Midostaurin added to 10-day decitabine, for patients unfit for intensive chemotherapy with AML and higher risk MDS, irrespective of FLT3 mutational status, does not improve outcome.

The treatment of older patients with acute myeloid leukemia (AML) considered unfit for receiving intensive chemotherapy is challenging. Based on the hypothesis that addition of the broad tyrosine kinase inhibitor (TKI) midostaurin could improve the response to hypomethylating agents, irrespective of FLT3 gene mutational status, we conducted a randomized phase II multicenter study to assess the tolerability and efficacy of the addition of midostaurin to a 10-day schedule of decitabine in unfit (i.e. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) ≥ 3) AML and higher risk myelodysplasia (MDS) patients (HOVON155 trial). In total, 140 eligible patients were randomly (1:1) assigned to treatment with 10-days of decitabine alone (N = 70) or combined with midostaurin (50 mg bid;starting the day following the last dose of decitabine), (N = 70). Addition of midostaurin was well tolerated and the number of AEs was comparable for both treatment arms. Early death rates (< 30 days) were similar as well (10%). In the decitabine plus midostaurin arm 24% reached CR/CRi, the median OS was 4.8 months and 1-yrs OS was 31% which compared with 34% CR/CRi, median OS of 7.4 months and 1-yrs OS of 37% for the decitabine alone group (NS). Thus, while the addition of midostaurin appears safe, it does not enhance therapeutic efficacy of decitabine in unfit AML patients.

A comprehensive review of phase 2/3 trials in osteoarthritis: an expert opinion.

INTRODUCTION: Osteoarthritis (OA) is a chronic, degenerative, and debilitating disease associated with significant long-term morbidity and disability. The pathogenesis of OA is not completely understood but involves an interplay between environmental risk factors, joint mechanics, abnormal pain pathways and upregulation of inflammatory signaling pathways. Current therapeutic options for patients are limited to conservative management, minimal pharmacological options or surgical management, with significant caveats to all approaches. AREAS COVERED: In this review, we have set out to investigate current phase II/III clinical trials by undertaking a PubMed search. Examined clinical trials have explored a myriad of potential therapeutics from conventional disease-modifying anti-rheumatic drugs and biologics usually used in the treatment of inflammatory arthritides, to more novel approaches targeting inflammatory pathways implicated in OA, cartilage degeneration or pain pathways. EXPERT OPINION: Unfortunately, most completed phase II/III clinical trials have shown little impact on patient pain scores, with the exception of the traditional DMARD methotrexate and Sprifermin. Methotrexate has been shown to be beneficial when used in the correct patient cohort (MRI proven synovitis). Sprifermin has the longest follow-up data of 5 years and has been shown to reduce loss of MRI-measured cartilage thickness and pain scores.

Emerging drugs in phase II and III clinical development for the treatment of alcohol use disorder.

INTRODUCTION: Alcohol Use Disorder (AUD) poses an ongoing significant global health burden. AUD is highly prevalent and affects not only the individuals with AUD, but also their communities and society at large. Even though pharmacotherapy is an integral part of AUD treatment, the few available substances show limited efficacy and limited clinical impact. Thus, there is a need for new innovative pharmacotherapeutic approaches. AREAS COVERED: This paper provides a comprehensive review of drugs approved for the treatment of AUD as well as those currently in phase II and III development. Data from recent clinical trials has been reviewed and supplemented by additional literature based on a systematic search of the PubMed database and clinical trials registries. Compounds discussed include disulfiram, naltrexone, nalmefene, acamprosat, baclofen, sodium oxybate, doxazosin, varenicline, zonisamide, gabapentin, apremilast, ibudilast, ivermectin, tolcapone, mifepristone, suvorexant, ketamine, psilocybin, semaglutide, oxytocin and cannabidiol. EXPERT OPINION: Even though the majority of the discussed compounds lack sufficient evidence to support their efficacy, multiple promising new treatment options are currently under investigation. Future research has to consider specific phenotypes and subgroups of AUD as well as a possible enhancement of the effects of psychotherapy through combination with pharmacotherapy. Practitioners should be encouraged to use available compounds to support existing therapeutic regimens.

An exploratory prospective phase II study of preoperative neoadjuvant bevacizumab and temozolomide for newly diagnosed glioblastoma.

PURPOSE: This multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bevacizumab (Bev) for newly diagnosed glioblastoma (GB). METHODS: Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1-5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The safety and efficacy were evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy. RESULTS: Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Median PFS and overall survival were 9.5 months and 16.5 months, respectively. CONCLUSION: Preoperative Bev and TMZ is safe as long as the instructions are followed. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively. TRIAL REGISTRATION NUMBER: UMIN000025579, jRCT1031180233 https://jrct.niph.go.jp/latest-detail/jRCT1031180233 . Registration Date: Jan. 16, 2017.

Mycovorax composti gen. nov., sp. nov., a member of the family Chitinophagaceae isolated from button mushroom compost.

Two Gram-stain-negative, aerobic, rod-shaped, orange-coloured bacterial strains, designated strain C216T and strain M2295, were isolated from mature mushroom compost from composting facilities in Victoria and South Australia, Australia, respectively. External structures such as flagella or pili were not observed on the cells under scanning electron microscopy. Optimal growth was found to occur at 45 °C, at pH 7.25 and in the absence of NaCl on Emerson's 350 YpSs medium. The genome sequence of strain C216T was 3 342 126 bp long with a G+C content of 40.5 mol%. Functional analysis of the genome of strain C216T revealed genes encoding chitinolytic and hemi-cellulolytic functions, with 166 predicted genes associated with carbohydrate metabolism (8.9% of the predicted genes). These functions are important for survival in the mushroom compost environment, which is rich in hemicelluloses. No antibiotic resistance genes were found in the genome sequence. The major fatty acids of strain C216T were iso-C15 : 0 (56.7%), iso-C17 : 0 3-OH (15.6%), C16 : 1 ω7c/iso-C15 : 0 2-OH (7.3%) and iso-C15 : 1 G (6.1%). The only respiratory quinone was MK-7. The major polar lipid of strain C216T was phosphatidylethanolamine, but three unidentified phospholipids, four unidentified aminophospholipids/aminolipids and one unidentified glycolipid were also detected. Phylogenetic analysis based on proteins encoded by the core genome (bac120, 120 conserved bacterial genes) showed that strain C216T forms a distinct lineage in the family Chitinophagaceae and that the closest identified relative is Niabella soli (69.69% ANI). These data demonstrate that strain C216T represents a novel genus and novel species within the family Chitinophagaceae, for which we propose the name Mycovorax composti. The type strain is C216T (=DSM 114558T=LMG 32998T).

Randomized phase II selection design with order constrained strata.

The exploratory nature of phase II trials makes it quite common to include heterogeneous patient subgroups with different prognoses in the same trial. Incorporating such patient heterogeneity or stratification into statistical calculation for sample size can improve efficiency and reduce sample sizes in single-arm phase II trials with binary outcomes. However, such consideration is lacking in randomized phase II trials. In this paper, we propose methods that can utilize some natural order constraints that may exist in stratified population to gain statistical efficiency for randomized phase II designs. For thoroughness and simplicity, we focus on the randomized phase II selection designs in this paper, although our method can be easily generalized to the randomized phase II screening designs. We consider both binary and time-to-event outcomes in our development. Compared with methods that do not use order constraints, our method is shown to improve the probabilities of correct selection or reduce sample size in our simulation and real examples.

A Bayesian phase II proof-of-concept design for clinical trials with longitudinal endpoints.

Existing phase II clinical trial designs focus on a single scalar endpoint, such as a binary, continuous, or survival endpoint. In some clinical trials, such as pain management studies, the efficacy endpoint of interest is measured longitudinally. We propose a Bayesian phase II design for such clinical trials. We model the longitudinal measurement process using Bayesian hierarchical model, where subject-specific trajectory shrinks toward the population trajectory to borrow information across subjects. The Bayesian penalized spline is used to model subject-specific and population trajectories without making strong parametric assumption on their shapes. We use the area under the curve of the trajectory as the summary of the treatment effect over time. The design takes a group sequential approach and takes into account both statistical significance and clinical relevance. Bayesian criteria is proposed to make interim and final decisions based on the evidence of statistical significance and clinical relevance. The proposed design is highly flexible and can accommodate trials with one or multiple longitudinal endpoints, as well as a longitudinal primary endpoint with a secondary endpoint. Simulation study shows that the proposed design is robust with desirable operating characteristics.

A flexible multi-metric Bayesian framework for decision-making in Phase II multi-arm multi-stage studies.

We propose a multi-metric flexible Bayesian framework to support efficient interim decision-making in multi-arm multi-stage phase II clinical trials. Multi-arm multi-stage phase II studies increase the efficiency of drug development, but early decisions regarding the futility or desirability of a given arm carry considerable risk since sample sizes are often low and follow-up periods may be short. Further, since intermediate outcomes based on biomarkers of treatment response are rarely perfect surrogates for the primary outcome and different trial stakeholders may have different levels of risk tolerance, a single hypothesis test is insufficient for comprehensively summarizing the state of the collected evidence. We present a Bayesian framework comprised of multiple metrics based on point estimates, uncertainty, and evidence towards desired thresholds (a Target Product Profile) for (1) ranking of arms and (2) comparison of each arm against an internal control. Using a large public-private partnership targeting novel TB arms as a motivating example, we find via simulation study that our multi-metric framework provides sufficient confidence for decision-making with sample sizes as low as 30 patients per arm, even when intermediate outcomes have only moderate correlation with the primary outcome. Our reframing of trial design and the decision-making procedure has been well-received by research partners and is a practical approach to more efficient assessment of novel therapeutics.

Transgender people in clinical trials of drugs and biologics: An analysis of ClinicalTrials.gov from 2007 to 2023.

AIMS: Transgender people have unmet health needs related to chronic conditions such as dementia, osteoporosis and hypertension. Community-driven advocacy increased transgender representation in phase III trials for pharmacological prevention of HIV, but the extent to which drug trials for other conditions have included transgender people is unknown. We investigated the extent to which trials of drugs and biologics represented transgender people across therapeutic areas on ClinicalTrials.gov. METHODS: Cross-sectional analysis of trials of drugs and biologics registered on ClinicalTrials.gov from 2007-2023. We included efficacy and effectiveness trials (phase II-IV) with transgender-related terms (e.g. 'transgend*'). We labelled trials as Inclusive or Exclusive of transgender people using the trial eligibility criteria. We compared trials (therapeutic area, trial design, enrolment), summarized trials registered from 2008 onward and characterized participant enrolment for Inclusive trials with primary trial publications. We summarized continuous data using median (range), categorical data using frequencies and percentages and compared trial characteristics using Fisher's exact test. RESULTS: Ninety-seven trials represented transgender people. Characteristics were similar between 85 Inclusive and 12 Exclusive trials. Among Inclusive trials, 58% focused on infectious diseases (e.g. treatment or prevention of HIV and COVID-19), 15% on mental health (e.g. post-traumatic stress disorder, substance use-related disorders), and the remainder focused on endocrine (9%), pain (5%), digestive system disorders (1%) and neoplasms (1%). Twenty (of 25) trials reported enrolment of transgender participants in primary trial publications or reported results. CONCLUSION: Transgender-inclusive trials have increased since 2008. Most trials focused on infectious diseases and mental health. Investigators should increase opportunities to include of transgender people in trials of drugs and biologics for chronic diseases.

The impacts of undetected nonadherence in phase II, III and post-marketing clinical trials: An overview.

AIMS: This research aims to provide an overview of the consequences of undiagnosed nonadherence (noninitiation, suboptimal implementation, nonpersistence) in randomized clinical trials (RCTs). METHODS: This research was conducted by combining a literature review and qualitative semistructured interviews with key opinion leaders. Based on this groundwork, the consequences of undiagnosed nonadherence in RCTs were summarized and reported in a figure. This study focused on phases II, III and post-marketing in ambulatory settings across a variety of therapeutic areas and indications. RESULTS: Various consequences of nonadherence in RCTs were investigated. In phase II, drug efficacy may be underestimated, variability in the outcomes may be high and a distorted picture of side effects could be reported, resulting in an uncertain impression of the investigational product's profile and complicating decision-making. The sponsor may need to increase the sample size of the upcoming phase III study to improve its power, representing additional costs, or even terminate the study. In phase III, similar phenomena may be observed, making demonstration of efficacy to the regulatory bodies more difficult. Lastly, after commercialization, a distortion in pharmacometrics may occur: the drug may underperform, prescriptions may be refilled less often than expected or extra expenses may be incurred by the payers. This can result in post-marketing dose reduction, new competitors coming into the market and, eventually, product withdrawal. CONCLUSIONS: This research highlighted the many potential adverse consequences of undiagnosed nonadherence in RCTs, including additional costs. Collecting accurate data appeared to be crucial for decision-making throughout the drug development process.