Assessing the Knowledge, Attitude, and Practice of Orthopedicians for Pain Management by Multimodal Approach: A Prospective, Cross-Sectional, and Observational Survey.

BACKGROUND: The routine use of multimodal analgesic modality results in lower pain scores with minimum side effects and opioid utilization. MATERIALS AND METHODS:  A prospective, cross-sectional, observational study was conducted among orthopedicians practicing across India to assess the professional opinions on using analgesics to manage orthopedic pain effectively. RESULTS:  A total of 530 orthopedicians participated in this survey. Over 50% of the participants responded that tramadol with or without paracetamol was the choice of therapy for acute pain. Nearly 50% of the participants mentioned that multimodal interventions can sometimes help to manage pain. A total of 55.6% of participants mentioned that using Non-steroidal anti-inflammatory drugs was the most common in their clinical practice, while 25.7% of participants mentioned that they used tramadol more commonly in their clinical practice. As per clinical efficacy ranking, the combination of tramadol plus paracetamol (44.3%) was ranked first among analgesic combinations, followed by aceclofenac plus paracetamol (40.0%). The severity of pain (62.6%) followed by age (60.6%) and duration of therapy (52.6%) were the most common factors that should be considered while prescribing tramadol plus paracetamol combination. Gastrointestinal and renal are reported as the most common safety concerns encountered with analgesics. CONCLUSION:  The combination of tramadol and paracetamol was identified as the most preferred choice of analgesics for prolonged orthopedic pain management.

Efficacy and Safety of Remogliflozin Etabonate, a New Sodium Glucose Co-Transporter-2 Inhibitor, in Patients with Type 2 Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Active-Controlled Trial.

BACKGROUND: Metformin is the first-line treatment for type 2 diabetes mellitus (T2DM), but many patients either cannot tolerate it or cannot achieve glycemic control with metformin alone, so treatment with other glucose-lowering agents in combination with metformin is frequently required. Remogliflozin etabonate, a novel agent, is an orally bioavailable prodrug of remogliflozin, which is a potent and selective sodium-glucose co-transporter-2 inhibitor. OBJECTIVE: Our objective was to evaluate the efficacy and safety of remogliflozin etabonate compared with dapagliflozin in subjects with T2DM in whom a stable dose of metformin as monotherapy was providing inadequate glycemic control. METHODS: A 24-week randomized, double-blind, double-dummy, active-controlled, three-arm, parallel-group, multicenter, phase III study was conducted in India. Patients aged ≥ 18 and ≤ 65 years diagnosed with T2DM, receiving metformin ≥ 1500 mg/day, and with glycated hemoglobin (HbA1c) levels ≥ 7 to ≤ 10% at screening were randomized into three groups. Every patient received metformin ≥ 1500 mg and either remogliflozin etabonate 100 mg twice daily (BID) (group 1, n = 225) or remogliflozin etabonate 250 mg BID (group 2, n = 241) or dapagliflozin 10 mg once daily (QD) in the morning and placebo QD in the evening (group 3, n = 146). The patients were followed-up at weeks 1 and 4 and at 4-week intervals thereafter until week 24. The endpoints included mean change in HbA1c (primary endpoint, noninferiority margin = 0.35), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), bodyweight, blood pressure, and fasting lipids. Treatment-emergent adverse events (TEAEs), safety laboratory values, electrocardiogram, and vital signs were evaluated. RESULTS: Of 612 randomized patients, 167 (group 1), 175 (group 2), and 103 (group 3) patients with comparable baseline characteristics completed the study. Mean change ± standard error (SE) in HbA1c from baseline to week 24 was - 0.72 ± 0.09, - 0.77 ± 0.09, and - 0.58 ± 0.12% in groups 1, 2, and 3, respectively. The difference in mean HbA1c of group 1 versus group 3 (- 0.14%, 90% confidence interval [CI] - 0.38 to 0.10) and group 2 versus group 3 (- 0.19%; 90% CI - 0.42 to 0.05) was noninferior to that in group 3 (p < 0.001). No significant difference was found between group 1 or group 2 and group 3 in change in FPG, PPG, and bodyweight. The overall incidence of TEAEs was comparable across study groups (group 1 = 32.6%, group 2 = 34.4%, group 3 = 29.5%), including adverse events (AEs) of special interest (hypoglycemic events, urinary tract infection, genital fungal infection). Most TEAEs were mild to moderate in intensity, and no severe AEs were reported. CONCLUSION: This study demonstrated the noninferiority of remogliflozin etabonate 100 and 250 mg compared with dapagliflozin, from the first analysis of an initial 612 patients. Remogliflozin etabonate therefore may be considered an effective and well-tolerated alternative treatment option for glycemic control in T2DM. TRIAL REGISTRATION: CTRI/2017/07/009121.

An Open-Label, Single-Period, Two-Stage, Single Oral Dose Pharmacokinetic Study of Remogliflozin Etabonate Tablet 100 and 250 mg in Healthy Asian Indian Male Subjects Under Fasting and Fed Conditions.

BACKGROUND AND OBJECTIVE: Remogliflozin etabonate is an orally available prodrug of remogliflozin, an inhibitor of renal sodium glucose co-transporter-2 (SGLT2) with antihyperglycemic activity. The present study was conducted to characterize the pharmacokinetic and safety profile of remogliflozin etabonate under fasting and fed conditions at single oral doses of 100 and 250 mg in healthy Asian Indian adults. METHODS: Sixty-five healthy, adult Asian Indian male subjects were enrolled in an open-label, two-stage, single-period pharmacokinetic study. Remogliflozin was given under fasting and/or fed conditions as a single oral dose of 100 or 250 mg. The plasma concentrations of remogliflozin etabonate, remogliflozin, and the metabolite GSK279782 were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were determined from the plasma concentration-time profile by non-compartmental analysis. Safety was assessed through monitoring of adverse events. Descriptive statistics were calculated and reported for all parameters. RESULTS: The plasma concentration profiles showed rapid absorption of the prodrug remogliflozin etabonate and rapid conversion to the active moiety, remogliflozin, which is then further metabolized to another active metabolite, GSK279782. The geometric mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were comparable for all three analytes between the fasted and fed state. The fed/fasted ratio for Cmax ranged from 0.77 to 1.44 at the 100 mg dose, and from 0.80 to 1.12 at the 250 mg dose. The fed/fasted ratio for AUC was 1.22 and 1.35 at 100 and 250 mg, respectively. An early time to Cmax (tmax) was observed for all three analytes while being administered in the fasted state. Both the Cmax and AUClast of all the three analytes increased in a dose-proportional manner under the fasted and fed states. The terminal half-life for remogliflozin ranged from 1.53 to 2.07 h. All three analytes had comparable terminal half-lives irrespective of dose levels or dietary conditions. CONCLUSIONS: Following single oral administration at 100 and 250 mg, remogliflozin etabonate showed favorable, linear pharmacokinetics. There were no clinically relevant food effects on the pharmacokinetics at both the 100 and 250 mg dose levels. Remogliflozin etabonate was well-tolerated without any safety concerns or hypoglycemic events. CLINICAL TRIAL REGISTRATION: Clinical Trial Registry-India identifier number CTRI/2017/10/010043.

Potential Risks and Mitigation Strategies During the Conduct of a Clinical Trial: An Industry Perspective.

BACKGROUND: Every phase of a clinical trial should be designed in compliance with good clinical practices by following all relevant regulatory guidelines. Patient safety, data integrity and ethics are an integral part of a successful clinical trial which must be considered. Therefore, risk monitoring is an essential tool to identify the risks associated with conduct of any trial. This article is a result of extensive research conducted by a reputed pharmaceutical company to identify the potential stages of risks associated with the conduct phase of trial that could impact the overall quality and safety of a trial. METHODS: The skillful and experienced team members of a reputed pharmaceutical company involved in conducting clinical trials underwent brainstorming sessions to assess and categorize the risks associated with each stage of conduct phase of a clinical trial. They also developed a mitigation plan based on their experiences, best practices and applicable guidance documents. RESULTS: During conduct phase, risks are associated with preparation of site master and trial master file, courier of study supply to site(s) including investigational product prior to site initiation visit, patient recruitment, telephonic monitoring, adverse or serious adverse event monitoring, site monitoring visit(s), collected case report form pages forward to data management vendor, data query clarification and site close-out visit. CONCLUSION: A close working relationship with all the persons associated with the clinical trial, timely monitoring and prospective mitigation planning is required for the conduct of a high quality trial.