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Efficacy and Safety of Fospropofol Disodium for Injection in General Anesthesia Induction for Adult Patients: A Phase 3 Trial.

ABSTRACT: Background: Fospropofol disodium for injection (Fospropofol_FD) is a prodrug that is metabolized into propofol to produce a general anesthesia effect when administered intravenously. Objective: This study aimed to assess the efficacy and safety of Fospropofol_FD in comparison with propofol medium/long-chain fat emulsion injections (propofol-MCT/LCT) for general anesthesia induction in adult patients undergoing elective surgeries. Setting: Nine academic medical centers in China. Method: This multicenter, randomized, double-blind, double-simulated, controlled, and non-inferiority trial evaluated 540 eligible adult patients randomly assigned (2:1) to the intervention (20 mg/kg Fospropofol_FD) or control (2 mg/kg propofol-MCT/LCT) groups. Main Outcome Measure: The primary efficacy endpoint was the success rate, defined as a Modified Observer's Assessment of Alertness/Sedation Scale score of 1 within 5 min after study drug administration. The safety endpoints consisted of adverse events (AEs) related to consciousness, cognitive function, hemodynamic status, liver and kidney function, and blood tests. Results: A total of 347 (96.3%) and 175 (97.2%) patients in the intervention and control groups, respectively, completed the study. The success rate for the primary outcome was 97.7% for both study drugs. The most frequent AEs in the intervention group were abnormal feeling (62.0%), blood pressure reduction (13.5%), and injection site pain (13.3%). No AEs related to consciousness and mental and cognitive functions or serious adverse events were reported. Conclusion: Fospropofol_FD (20 mg/kg) is not inferior to propofol-MCT/LCT (2 mg/kg) in general anesthesia induction for American Society of Anesthesiologists (ASA) physical status I-II adult patients undergoing elective surgeries. It is safe and effective for clinical use under anesthesiologist monitoring. Impact on Practice Statement: Fospropofol_FD can produce a general anesthesia effect and reduce the incidence of pain at the site of injection.

SUBMITTER: Wu CM

PROVIDER: S-EPMC8473892 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectivesASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD).MethodsAdults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses.ResultsOf 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%).DiscussionThis study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD.Trial registration informationClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24).Classification of evidenceThis study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

Project description:BackgroundHSK3486 (ciprofol) is a 2,6-disubstituted phenol derivative that acts like propofol as an agonist at the gamma-aminobutyric acid-A (GABA A ) receptor.ObjectiveTo investigate the efficacy and safety of HSK3486 for general anaesthesia induction and maintenance.DesignA single-blinded, randomised, parallel-group, phase 3 trial.SettingInvolving 10 study centres, from November 24, 2020 to January 25, 2021.PatientsA total of 129 patients undergoing nonemergency, noncardiothoracic, and nonneurosurgical elective surgery.InterventionPatients were randomly assigned at a 2:1 ratio into HSK3486 or propofol groups, to receive HSK3486 (0.4 mg kg -1 ) or propofol (2.0 mg kg -1 ) for induction before a maintenance infusion at initial rates of 0.8 and 5.0 mg kg -1 h -1 , and were adjusted to maintain a bispectral index (BIS) of 40-60 until the end of surgery.Main outcome measuresNoninferiority between the drugs was evaluated as the lower limit of the 95% confidence interval (CI) for the between-group difference in the success rate of anesthetic maintenance (primary outcome) >-8%. Secondary outcomes included successful anaesthetic induction, full alertness and spontaneous breathing recovery, time until leaving the postanaesthesia care unit and changes in BIS. Safety profiles were also measured.ResultsOf 129 enrolled patients, 128 completed the trial, with 86 in the HSK3486 group and 42 in the propofol group. The success rate for the maintenance of general anaesthesia was 100% for both groups, and noninferiority of HSK3486 was confirmed (95% CI -4.28% to 8.38%). No significant differences were found between the two groups of patients with regard to secondary outcomes (all P > 0.05). There appeared to be a comparable incidence of treatment for emergency adverse events (TEAEs) (80.2% vs. 81.0%, P = 1.000) and drug-related TEAEs (57.0% vs. 64.3%, P = 0.451) in the HSK3486 and propofol groups.ConclusionHSK3486 had a noninferior efficacy profile compared to propofol, exhibiting excellent tolerance.Trial registrationClinicaltrials.gov, identifier: NCT04511728.

Project description:: Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. The vinca alkaloid vincristine is a standard component of chemotherapy regimens used to treat ALL, because of its well-defined mechanism of action, demonstrated anticancer activity, and ability to be combined with other agents. However, the dosage of vincristine is frequently capped because of neurotoxicity concerns, and patients with large body surface areas are, therefore, almost always underdosed. Liposomal formulations have the ability to "passively" accumulate at sites of increased vasculature permeability and reduce the adverse effects of encapsulated relative to free drug. Vincristine sulfate liposome injection (VSLI) is a sphingomyelin/cholesterol-based liposome-encapsulated formulation that is delivered weekly in a 1-hour infusion. Based on the pharmacokinetics of the liposomal delivery system, vincristine is slowly released from the liposome and delivered into the tissues more efficiently than with the standard preparation, allowing a higher dose. This increase in therapeutic index from reduced toxicity is a valuable difference between the two formulations. VSLI is indicated for the treatment of adults with second or greater relapse and clinically advanced Philadelphia chromosome-negative ALL. For the first time, studies will be able to exploit the delivery of higher and uncapped doses of vincristine in randomized studies comparing first-line chemotherapy with standard vincristine versus VSLI in both ALL and lymphoma to determine whether VSLI is superior to conventional vincristine.This review summarizes the development of vincristine sulfate liposome injection, a new formulation of vincristine. The pharmacokinetics of liposomal drug delivery are examined, the limitations and advantages of conventional and liposomal vincristine are compared, and the use of vincristine sulfate liposome injection in clinical trials and case studies is included. Clinicians will be informed of a new chemotherapy agent that is indicated for the treatment of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia, whose disease has relapsed two or more times or whose leukemia has progressed after two or more regimens of antileukemia therapy.

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Efficacy and Safety of Fospropofol Disodium for Injection in General Anesthesia Induction for Adult Patients: A Phase 3 Trial.

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