Why admixture matters in genetically-guided therapy: missed targets in the COAG and EU-PACT trials.
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ABSTRACT:
SUBMITTER: Duconge J
PROVIDER: S-EPMC4770896 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Advanced therapies are emerging as an important class of medicinal products; among these, gene therapies are advancing at an exceptional rate. However, one of the major challenges for gene therapies relates to the additional regulatory requirements for genetically modified organisms. In this paper, we provide an overview of the regulatory requirements for genetically modified organisms in the European Union, Japan, and the United States. We share our experience in managing these requirements and their impact on the adeno-associated virus gene therapies that are under development at Pfizer. Specifically, we discuss the relative complexity of the approval process and the impact of risk assessment expectations on the clinical development of genetically modified organisms. We also compare the regulatory processes and timelines of various regions based on our experience with adeno-associated viral vectors. Finally, we propose that genetically modified organisms, for which pathogenicity and replication competency are well controlled, should be regulated solely under medicinal product regulations and be exempt from additional requirements for genetically modified organisms. Even if an exemption is not implemented, it should still be possible to significantly reduce the sponsor and agency burden by simplifying and harmonizing documentation and data requirements as well as timelines for applications for genetically modified organisms.
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Project description:PurposeInfections due to severe neutropenia are the most common therapy-associated causes of mortality in patients with acute myeloid leukemia (AML). New strategies to lessen the severity and duration of neutropenia are needed.MethodsCytarabine is commonly used for AML consolidation therapy; we compared high- and intermediate-dose cytarabine administration on days 1, 2, and 3 (AC-123) versus days 1, 3, and 5 (AC-135) in consolidation therapy of AML. Recently, clinical trials demonstrated that high-dose AC-123 resulted in a shortened white blood cell (WBC) recovery time compared with high-dose AC-135. Our main hypothesis is that this is also the case for different cytarabine dosage, granulocyte colony-stimulating factor (G-CSF) administration, and cycle lengths. We analyzed 334 treatment schedules on virtual cohorts of digital twins.ResultsComparison of 32,565 simulated consolidation cycles resulted in a reduction in the WBC recovery time for AC-123 in 99.6% of the considered cycles (median reduction 3.5 days) without an increase in the number of leukemic blasts (lower value in 94.2% of all cycles), compared to AC-135.ConclusionOur numerical study supports the use of AC-123 plus G-CSF as standard conventional AML consolidation therapy to reduce the risk for life-threatening infectious complications.
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Project description:Self-reported pain intensity, frequently used as an outcome in randomized clinical trials (RCTs) of chronic pain, is often highly variable and could be associated with multiple baseline factors. Thus, the assay sensitivity of pain trials (ie, the ability of the trial to detect a true treatment effect) could be improved by including prespecified baseline factors in the primary statistical model. The objective of this focus article was to characterize the baseline factors included in statistical analyses of chronic pain RCTs. Seventy-three RCTs published between 2016 and 2021 that investigated interventions for chronic pain were included. The majority of trials identified a single primary analysis (72.6%; n = 53). Of these, 60.4% (n = 32) included one or more covariates in the primary statistical model, most commonly baseline value of the primary outcome, study site, sex, and age. Only one of the trials reported information regarding associations between covariates and outcomes (ie, information that could inform prioritization of covariates for prespecification in future analyses). These findings demonstrate inconsistent use of covariates in the statistical models in chronic pain clinical trials. Prespecified adjustments for baseline covariates that could increase precision and assay sensitivity should be considered in future clinical trials of chronic pain treatments. PERSPECTIVE: This review demonstrates inconsistent inclusion and potential underutilization of covariate adjustment in analyses of chronic pain RCTs. This article highlights areas for possible improvement in design and reporting related to covariate adjustment to improve efficiency in future RCTs.
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Project description:The vitamin D receptor is expressed in most tissues of the body - and the cancers that arise from those tissues. The vitamin D signaling pathway is active in those tissues and cancers. This is at least consistent with the hypothesis that perturbing this signaling may have a favorable effect on the genesis and growth of cancers. Epidemiologic data indicate that vitamin D signaling may be important in the initiation and outcome of a number of types of cancer. Many studies have shown that calcitriol (1,25 dihydroxycholecalciferol) and other vitamin D compounds have antiproliferative, pro-apoptotic, anti-cell migration and antiangiogenic activity in a number of preclinical studies in many different cancer types. Unfortunately, the assessment of the activity of calcitriol or other vitamin D analogues in the treatment of cancer, as single agents or in combination with other anticancer agents has been stymied by the failure to adhere to commonly accepted principles of drug development and clinical trials conduct.
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Project description:BACKGROUND:Perfectionism can become a debilitating condition that may negatively affect functioning in multiple areas, including mental health. Prior research has indicated that internet-based cognitive behavioral therapy can be beneficial, but few studies have included follow-up data. OBJECTIVE:The objective of this study was to explore the outcomes at follow-up of internet-based cognitive behavioral therapy with guided self-help, delivered as 2 separate randomized controlled trials conducted in Sweden and the United Kingdom. METHODS:In total, 120 participants randomly assigned to internet-based cognitive behavioral therapy were included in both intention-to-treat and completer analyses: 78 in the Swedish trial and 62 in the UK trial. The primary outcome measure was the Frost Multidimensional Perfectionism Scale, Concern over Mistakes subscale (FMPS CM). Secondary outcome measures varied between the trials and consisted of the Clinical Perfectionism Questionnaire (CPQ; both trials), the 9-item Patient Health Questionnaire (PHQ-9; Swedish trial), the 7-item Generalized Anxiety Disorder scale (GAD-7; Swedish trial), and the 21-item Depression Anxiety Stress Scale (DASS-21; UK trial). Follow-up occurred after 6 months for the UK trial and after 12 months for the Swedish trial. RESULTS:Analysis of covariance revealed a significant difference between pretreatment and follow-up in both studies. Intention-to-treat within-group Cohen d effect sizes were 1.21 (Swedish trial; 95% CI 0.86-1.54) and 1.24 (UK trial; 95% CI 0.85-1.62) for the FMPS CM. Furthermore, 29 (59%; Swedish trial) and 15 (43%; UK trial) of the participants met the criteria for recovery on the FMPS CM. Improvements were also significant for the CPQ, with effect sizes of 1.32 (Swedish trial; 95% CI 0.97-1.66) and 1.49 (UK trial; 95% CI 1.09-1.88); the PHQ-9, effect size 0.60 (95% CI 0.28-0.92); the GAD-7, effect size 0.67 (95% CI 0.34-0.99); and the DASS-21, effect size 0.50 (95% CI 0.13-0.85). CONCLUSIONS:The results are promising for the use of internet-based cognitive behavioral therapy as a way of targeting perfectionism, but the findings need to be replicated and include a comparison condition.
| S-EPMC5945983 | biostudies-literature
Project description:ObjectiveTo identify the availability of results for trials registered on the European Union Clinical Trials Register (EUCTR) compared with other dissemination routes to understand its value as a results repository.DesignCross sectional audit study.SettingEUCTR protocols and results sections, data extracted 1-3 December 2020.PopulationRandom sample of 500 trials registered on EUCTR with a completion date of more than two years from the beginning of searches (ie, 1 December 2018).Main outcome measuresProportion of trials with results across the examined dissemination routes (EUCTR, ClinicalTrials.gov, ISRCTN registry, and journal publications), and for each dissemination route individually. Prespecified secondary outcomes were number and proportion of unique results, and the timing of results, for each dissemination route.ResultsIn the sample of 500 trials, availability of results on EUCTR (53.2%, 95% confidence interval 48.8% to 57.6%) was similar to the peer reviewed literature (58.6%, 54.3% to 62.9%) and exceeded the proportion of results available on other registries with matched records. Among the 383 trials with any results, 55 (14.4%, 10.9% to 17.9%) were only available on EUCTR. Also, after the launch of the EUCTR results database, median time to results was fastest on EUCTR (1142 days, 95% confidence interval 812 to 1492), comparable with journal publications (1226 days, 1074 to 1551), and exceeding ClinicalTrials.gov (3321 days, 1653 to undefined). For 117 trials (23.4%, 19.7% to 27.1%), however, results were published elsewhere but not submitted to the EUCTR registry, and no results were located in any dissemination route for 117 trials (23.4%, 19.7% to 27.1).ConclusionsEUCTR should be considered in results searches for systematic reviews and can help researchers and the public to access the results of clinical trials, unavailable elsewhere, in a timely way. Reporting requirements, such as the EU's, can help in avoiding research waste by ensuring results are reported. The registry's true value, however, is unrealised because of inadequate compliance with EU guidelines, and problems with data quality that complicate the routine use of the registry. As the EU transitions to a new registry, continuing to emphasise the importance of EUCTR and the provision of timely and complete data is critical. For the future, EUCTR will still hold important information from the past two decades of clinical research in Europe. With increased efforts from sponsors and regulators, the registry can continue to grow as a source of results of clinical trials, many of which might be unavailable from other dissemination routes.
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Project description:Statin adherence is often limited by side effects. The SLCO1B1*5 variant is a risk factor for statin side effects and exhibits statin-specific effects: highest with simvastatin/atorvastatin and lowest with pravastatin/rosuvastatin. The effects of SLCO1B1*5 genotype guided statin therapy (GGST) are unknown. Primary care patients (n = 58) who were nonadherent to statins and their providers received SLCO1B1*5 genotyping and guided recommendations via the electronic medical record (EMR). The primary outcome was the change in Beliefs about Medications Questionnaire, which measured patients' perceived needs for statins and concerns about adverse effects, measured before and after SLCO1B1*5 results. Concurrent controls (n = 59) were identified through the EMR to compare secondary outcomes: new statin prescriptions, statin utilization, and change in LDL-cholesterol (LDL-c). GGST patients had trends (p = 0.2) towards improved statin necessity and concerns. The largest changes were the "need for statin to prevent sickness" (p < 0.001) and "concern for statin to disrupt life" (p = 0.006). GGST patients had more statin prescriptions (p < 0.001), higher statin use (p < 0.001), and greater decrease in LDL-c (p = 0.059) during follow-up. EMR delivery of SLCO1B1*5 results and recommendations is feasible in the primary care setting. This novel intervention may improve patients' perceptions of statins and physician behaviors that promote higher statin adherence and lower LDL-c.
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Project description:International trials have shown that CD4+ T-cell-guided structured treatment interruptions (STI) of antiretroviral therapy (ART) lead to worse outcomes than continuous treatment. We simulated continuous ART and STI strategies with higher CD4+ T-cell interruption/reintroduction thresholds than those assessed in actual trials.Using a model of HIV, we simulated cohorts of African adults with different baseline CD4+ T-cell counts (< or = 200; 201-350; and 351-500 cells/microl). We varied ART initiation criteria (immediate; CD4+ T-cell count < 350 cells/microl or > or = 350 cells/microl with severe HIV-related disease; and CD4+ T-cell count <200 cells/microl or > or = 200 cells/microl with severe HIV-related disease), and ART interruption/reintroduction thresholds (350/250; 500/350; and 700/500 cells/microl). First-line therapy was non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and second-line therapy was protease inhibitor (PI)-based.STI generally reduced life expectancy compared with continuous ART. Life expectancy increased with earlier ART initiation and higher interruption/reintroduction thresholds. STI reduced life expectancy by 48-69 and 11-30 months compared with continuous ART when interruption/reintroduction thresholds were 350/250 and 500/350 cells/microl, depending on ART initiation criteria. When patients interrupted/reintroduced ART at 700/500 cells/microl, life expectancies ranged from 2 months lower to 1 month higher than continuous ART. STI-related life expectancy increased with decreased risk of virological resistance after ART interruptions.STI with NNRTI-based regimens was almost always less effective than continuous treatment, regardless of interruption/reintroduction thresholds. The risks associated with STI decrease only if patients start ART earlier, interrupt/reintroduce treatment at very high CD4+ T-cell thresholds (700/500 cells/microl) and use first-line medications with higher resistance barriers, such as PIs.
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Project description:Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.
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Project description:Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples.The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21(CIP1/WAF1), hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21(CIP1/WAF1) attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors.Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors.
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