The safety, tolerability and mortality reduction efficacy of remdesivir; based on randomized clinical trials, observational and case studies reported safety outcomes: an updated systematic review and meta-analysis.
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SUBMITTER: Santenna C
PROVIDER: S-EPMC8477695 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Phase I experts recommend revisiting dose-limiting toxicity (DLT) definition to include chronic and cumulative toxicities induced by new molecularly targeted therapies. Patient's assessment of late toxicities' tolerability is, however, unknown.A prospective survey on adverse events (AEs) tolerability on 23 National Cancer InstituteCommon Terminology Criteria for Adverse Event, Version 4 (NCI-CTCAE.v4) items was conducted at Gustave Roussy's Phase I department. Patients' maximum tolerability duration was recorded at baseline, during trial and at trial completion. Results were compared with the corresponding physicians' survey.52 patients enrolled in 27 Phase I trials between May 2014 and November 2015 completed 102 forms. At baseline, the most feared G2/G3 AEs were haematuria (74%), vomiting (71%) and hyperglycemia (64%)/dry mouth (94%), hyperglycemia (92%) and vomiting (92%). At trial completion, the most feared G2/G3 AEs were personality change (83.3%), haematuria (82%) and fever (80%)/dry mouth, fever and dizziness (100% each). Tolerability score did not differ over time. More previous treatments and occurrence of severe AEs were associated with better tolerability at study completion (p=0.0234 and p=0.0153, respectively, in multivariate analysis). Patient's tolerability differed from physician's assessment.AEs considered intolerable by patients are toxicities that directly impact their quality of life and differ from those feared by physicians or included in DLT definition. Patient-reported tolerability of AEs may help in optimising drug development.
| S-EPMC5519806 | biostudies-other
Project description:Remdesivir (RDV), a single diastereomeric monophosphoramidate prodrug that inhibits viral RNA polymerases, has potent in vitro antiviral activity against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). RDV received the US Food and Drug Administration (FDA)'s emergency use authorization in the United States and approval in Japan for treatment of patients with severe coronavirus disease 2019 (COVID-19). This report describes two phase I studies that evaluated the safety and pharmacokinetics (PKs) of single escalating and multiple i.v. doses of RDV (solution or lyophilized formulation) in healthy subjects. Lyophilized formulation was evaluated for potential future use in clinical trials due to its storage stability in resource-limited settings. All adverse events were grade 1 or 2 in severity. Overall, RDV exhibited a linear profile following single-dose i.v. administration over 2 hours of RDV solution formulation across the dose range of 3-225 mg. Both lyophilized and solution formulations provided comparable PK parameters. High intracellular concentrations of the active triphosphate (~ 220-fold to 370-fold higher than the in vitro half-maximal effective concentration against SARS-CoV-2 clinical isolate) were achieved following infusion of 75 mg or 150 mg lyophilized formulation over 30 minutes or 2 hours. Following multiple-doses of RDV 150 mg once daily for 7 or 14 days, RDV exhibited a PK profile similar to single-dose administration. Metabolite GS-441524 accumulated ~ 1.9-fold after daily dosing. Overall, RDV exhibited favorable safety and PK profiles that supported once-daily dosing.
| S-EPMC7361781 | biostudies-literature
Project description:PurposeStudies investigating efficacy and safety of bevacizumab in pterygium have increased and reported controversial results. Thus, we updated this meta-analysis to clarify the issue.MethodsStudies were selected through search of the databases Embase, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) from their inception up until June 2017. The pooled risk ratio (RR) and 95% confidence interval (CI) were calculated for recurrence and complication rates by using random effects model.Results1045 eyes in 18 randomized controlled trials (RCTs) enrolled. Overall, the pooled estimate showed a statistically significant effect of bevacizumab on the reduction of recurrence (RR 0.74, 95% CI 0.56-0.97, P=0.03). Subgroup analyses presented significant results beneficial to bevacizumab (primary pterygium group, RR 0.53, 95% CI 0.33-0.83, P=0.006; conjunctival autograft group, RR 0.48, 95% CI 0.25-0.91, P=0.02; and follow-up longer than 12 months group, RR 0.36, 95% CI 0.13-0.99, P=0.05). No statistically significant difference was observed in complication rates.ConclusionsApplication of bevacizumab showed a statistically significant decrease in recurrence rate following removal of primary pterygia, or in cases with conjunctival autograft, or with follow-up longer than 12 months, while complications were not increased.
| S-EPMC6145151 | biostudies-literature
Project description:ObjectivesWe performed a systematic review and network meta-analysis of randomized controlled trials (RCTs) to provide updated information regarding the clinical efficacy of remdesivir in treating coronavirus disease 2019 (COVID-19).MethodsPubMed, Embase, Cochrane Library, clinical trial registries of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched for relevant articles published up to 18 November 2020.ResultsFive RCTs, including 13 544 patients, were included in this meta-analysis. Among them, 3839 and 391 patients were assigned to the 10 day and 5 day remdesivir regimens, respectively. Patients receiving 5 day remdesivir therapy presented greater clinical improvement than those in the control group [OR = 1.68 (95% CI 1.18-2.40)], with no significant difference observed between the 10 day and placebo groups [OR = 1.23 (95% CI 0.90-1.68)]. Patients receiving remdesivir revealed a greater likelihood of discharge [10 day remdesivir versus control: OR = 1.32 (95% CI 1.09-1.60); 5 day remdesivir versus control: OR = 1.73 (95% CI 1.28-2.35)] and recovery [10 day remdesivir versus control: OR = 1.29 (95% CI 1.03-1.60); 5 day remdesivir versus control: OR = 1.80 (95% CI 1.31-2.48)] than those in the control group. In contrast, no mortality benefit was observed following remdesivir therapy. Furthermore, no significant association was observed between remdesivir treatment and an increased risk of adverse events.ConclusionsRemdesivir can help improve the clinical outcome of hospitalized patients with COVID-19 and a 5 day regimen, instead of a 10 day regimen, may be sufficient for treatment. Moreover, remdesivir appears as tolerable as other comparators or placebo.
| S-EPMC8083728 | biostudies-literature
Project description:Purpose The purpose of this study was to evaluate the safety and tolerability profile of drugs used for treating common eye disorders when applied to normal healthy volunteers (NHVs) as explored in phase 1 trials. Subjects and Methods A total of 166 NHVs were identified in six phase 1 trials, examined in a retrospective analysis. The primary endpoints were visual comfort (by ocular comfort index, OCI) and safety (laboratory evaluations, vital signs (VS), visual acuity (VA), intraocular pressure (IOP), lissamine green and fluorescein staining, conjunctival hyperemia, chemosis, and adverse events’ incidence (AE)). Results Compared to baseline, 75.9%, 40.4% and 73.7% of NHV (for lubricant, hypotensive and antibiotic treatments, respectively) improved their OCI score by their final visit. Laboratory evaluations and VS were within normal ranges in 88% of NHV. Similar results were found for VA, corneal and conjunctival staining, and chemosis. IOP decreased significantly in the hypotensive agents’ group, trace to mild hyperemia was reported in 32.1%, 27.1%, and 6.8%, respectively. Additionally, lubricant and hypotensive investigational drugs (ID) had a lower risk of incidence of AE than approved drugs (OR 0.856, 95% CI [0.365, 1.999] and 0.636, 95% CI [0.096, 4.197], respectively). Meanwhile, on antibiotic drugs, the risk for ID-related AE was higher (OR 1.313, 95% CI [0.309, 5.583]). Conclusion Phase 1 trials are important in order to ensure the safety and tolerability of ophthalmic medications. This study demonstrates that NHVs do not face a significant risk of harm in these studies, since 98% of the reported AE were mild, and all AE were resolved by the end of the study in which they appeared. Trial Registration This is a retrospective study of six previously conducted clinical trials, registered on clinicaltrials.gov with the following registration IDs: NCT04081610, NCT03524157, NCT03520348, NCT03966365, NCT03965052 and, NCT03519516.
| S-EPMC8544558 | biostudies-literature
Project description:Aims/introductionThis meta-analysis aimed to evaluate the efficacy and safety/tolerability of imeglimin, a novel oral antihyperglycemic agent, administered as monotherapy and adjunctive therapy in patients with type 2 diabetes mellitus.Materials and methodsParallel-group randomized controlled trials comparing imeglimin with placebo in adults with type 2 diabetes mellitus were included. Risk ratios or weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated using random effects models. The primary outcome for efficacy was the change in glycated hemoglobin (HbA1c). Secondary outcomes included other efficacy-related outcomes, specific adverse events, and changes in body weight and lipid parameters.ResultsNine randomized controlled trials (n = 1,655) were included. When analyzed by dose, there was a significant difference in glycated hemoglobin (%) between imeglimin monotherapy and placebo at doses >1,000 mg twice daily (1,000 mg: studies N = 3, patients n = 517, WMD = -0.714, P < 0.001; 1,500 mg: N = 5, n = 448, WMD = -0.531, P = 0.020; 2,000 mg: N = 1, n = 149, WMD = -0.450, P = 0.005). Imeglimin adjunctive therapy significantly improved glycated hemoglobin over placebo at doses of 1,000 mg (N = 1, n = 214, WMD = -0.600, P < 0.001) and 1,500 mg (N = 2, n = 324, WMD = -0.576, P < 0.001). Subgroup analysis of the primary outcome showed that imeglimin was effective regardless of chronic kidney disease category, with studies carried out in Japan and in patients with lower body mass index showing a trend toward improved imeglimin efficacy. There were no significant differences between imeglimin and placebo in the risk of all-cause discontinuation and the proportion of patients who presented with at least one adverse event.ConclusionsImeglimin is efficacious, safe, and well tolerated as monotherapy and adjunctive therapy.
| S-EPMC10583642 | biostudies-literature
Project description:Data suggest that for newly approved cancer drugs safety and tolerability are worse than in control arms of registration trials. Less is known about the balance between efficacy and toxicity of drugs studied in unselected phase 3 randomized controlled trials (RCTs) including those not resulting in regulatory approval. We searched Clinicaltrials.gov to identify phase 3 RCTs in patients with advanced breast, colorectal, lung, or prostate cancer completed between January 2005 and October 2016. We extracted efficacy and safety data from publications. For efficacy hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were extracted. For safety, we computed odds ratios (ORs) and 95% confidence intervals (CIs) for toxic death, treatment discontinuation without progression and commonly reported grade 3/4 adverse events (AEs). Data were then pooled in a meta-analysis. Of 377 RCTs identified initially, 143 RCTs comprising 88,603 patients were included in the analysis. Of these, 79 (57%) trials met their primary endpoint. Compared to control groups, both PFS (HR 0.80; 95% CI 0.78-0.82) and OS (HR 0.87; 95% CI 0.85-0.89) were improved with experimental drugs. Toxic death (OR 1.14; 95% CI 1.03-1.27), treatment discontinuation without progression (OR 1.64; 95% CI 1.56-1.71) and grade 3/4 AEs were also more common with experimental drugs compared to respective control group therapy. Just over half of phase 3 RCTs in common solid tumors met their primary endpoint and in nearly half, experimental therapy had worse safety compared to control arms.
| S-EPMC8149406 | biostudies-literature
Project description:Duloxetine is a serotonin-norepinephrine reuptake inhibitor approved for the treatment of patients affected by major depressive disorder (MDD), generalized anxiety disorder (GAD), neuropathic pain (NP), fibromyalgia (FMS), and stress incontinence urinary (SUI). These conditions share parallel pathophysiological pathways, and duloxetine treatment might be an effective and safe alternative. Thus, a systematic review was conducted following the 2009 Preferred Reporting Items (PRISMA) recommendations and Joanna Briggs Institute Critical (JBI) Appraisals guidelines. Eighty-five studies focused on efficacy, safety, and tolerability of duloxetine were included in our systematic review. Studies were subdivided by clinical condition and evaluated individually. Thus, 32 studies of MDD, 11 studies of GAD, 19 studies of NP, 9 studies of FMS, and 14 studies of SUI demonstrated that the measured outcomes indicate the suitability of duloxetine in the treatment of these clinical conditions. This systematic review confirms that the dual mechanism of duloxetine benefits the treatment of comorbid clinical conditions, and supports the efficacy, safety, and tolerability of duloxetine in short- and long-term treatments.
| S-EPMC7644852 | biostudies-literature
Project description:Introduction: Severe, often sudden-onset headache is the principal presenting symptoms of aneurysmal subarachnoid hemorrhage (aSAH). We hypothesized that gabapentin would be safe and tolerable for aSAH-induced headaches and would reduce concurrent opioid use. Methods: We performed a single-center, double-blind, randomized, placebo-controlled trial (registered at ClinicalTrials.gov; NCT02330094) from November 24, 2014, to June 24, 2017, where aSAH patients received either dose-escalating gabapentin or oral placebo, both alongside a standard of care pain regimen. After 7 days, patients had the option to continue in an open-label period until 14 days after enrollment or until discharge from the intensive care unit. Our primary endpoint was the efficacy of gabapentin in reducing headache numeric pain scores and opioid usage in patients with aSAH compared to the placebo group. We identified 63 potential patients with aSAH for the study. After applying stringent exclusion criteria, 16 eligible patients were enrolled into one of two arms. Results: The study ended prematurely after reaching a pre-specified funding period and an unexpected drop in aSAH cases. There was a trend toward lower headache numeric pain scores and opioid use in the gabapentin treated arm; however this was not significantly different. Gabapentin was well tolerated by participants and no adverse effects were reported. Conclusions: While there was a trend toward lower pain scores and opioid requirement in the gabapentin group, the study was underpowered to detect a difference. Larger multicenter trials are required to evaluate the efficacy of gabapentin to reduce opioid requirements after aSAH.
| S-EPMC7399216 | biostudies-literature
Project description:An open label, phase IIa study conducted in Ethiopia evaluated the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of the phosphatidylinositol 4-kinase inhibitor MMV390048 in Plasmodium vivax malaria. The study was not completed for operational reasons and emerging teratotoxicity data. For the eight adult male patients enrolled, adequate clinical and parasitological response at day 14 (primary endpoint) was 100% (8/8). Asexual parasites and gametocytes were cleared in all patients by 66 and 78 hours postdose, respectively. There were two recurrent P. vivax infections (days 20 and 28) and a new Plasmodium falciparum infection (day 22). MMV390048 exposure in P. vivax patients was lower than previously observed for healthy volunteers. Mild adverse events, mainly headache and gastrointestinal symptoms, were reported by eight patients. Single-dose MMV390048 (120 mg) rapidly cleared asexual parasites and gametocytes in patients with P. vivax malaria and was well tolerated.
| S-EPMC9833083 | biostudies-literature