Phase IV Studies: What Clinicians Need to Know!

Phase IV trials, also known as postmarketing safety and efficacy studies and postmarketing surveillance (PMS) studies, occur after a drug or medical device has received regulatory approval and is available in the market. These trials are designed to collect additional information regarding the product's safety, efficacy, and prolonged effects in a larger and more diverse patient population. The foremost goal of phase IV trials is to detect any rare or long-term adverse effects that may not have been identified during the prior phases of clinical development. During phase IV trials, pharmaceutical companies, academic institutions, or other research organizations conduct studies to evaluate various aspects of the product, including its real-world effectiveness, optimal use, and any potential safety concerns. The regulatory agencies play a role in overseeing these trials to ensure that they are conducted ethically and in compliance with good clinical practice (GCP) guidelines.

Naftifine: A Topical Allylamine for Superficial Dermatophytosis.

Dermatophytosis is a very common public health problem with high prevalence. Dermatophytes are a highly specialized set of filamentous fungi, which are adapted to keratinized tissues of humans and animals. Dermatophytosis is the most common fungal infection worldwide, affecting approximately 20-25% of the world's population. The etiological agents of dermatophytosis, called dermatophytes, change with geography and socioeconomic status. Trichophyton rubrum (T. rubrum) is the prime species for skin and nail infections followed by T. mentagrophytes/ T. interdigital complex. There is a shift from T. rubrum to T. mentagrophytes in India for superficial fungal infections. In order to deal with fungal infections, treatment strategies involve the use of systemic antifungals and/or topical antifungal agents. Naftifine is a synthetic allylamine antifungal first reported in 1974 and in 1985 became the first commercially available allylamine. The highly lipophilic nature of allylamine allows efficient penetration and reasonably high concentrations in the stratum corneum (SC) and hair follicles. Naftifine is fungicidal as well as fungistatic. The higher efficacy rates of allylamines over imidazoles for the treatment of fungal infections, even for months after cessation of treatment, is thought to be due to their fungicidal effect, as well as to potentially greater keratin binding and slower release from the SC. The effectiveness of naftifine is also demonstrated against various bacteria belonging to both gram-negative and gram-positive classes. The antiinflammatory property of naftifine has been reported in various preclinical studies where it has been shown to target the prostaglandin pathway. Naftifine 1 and 2% gel and cream is approved by The United States Food and Drug Administration (USFDA), recently naftifine has been approved in India by the Indian regulatory authority Drug Controller General of India (DCGI) for the treatment of dermatophytosis. Naftifine 2% also appears to be a promising treatment, requiring fewer applications than the 1% formulation. Naftifine appears to be effective in a single dose and has a shorter treatment duration than azoles. Naftifine demonstrated its efficacy and safety in various clinical studies of tinea infections. Naftifine offers a very useful and promising option for treating dermatophytosis.

Current Role of Dapagliflozin in Clinical Practice.

Dapagliflozin is the first in a novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors which was approved by USFDA in management of type 2 diabetes mellitus (T2DM) as an adjunct to diet and exercise to improve glycemic control in adults initially, followed by to reduce the risk of hospitalization for heart failure (HHF) in adults with T2DM and established cardiovascular disease or multiple cardiovascular risk factors. Most recently, it is approved to reduce the risk of cardiovascular death and in adults with heart failure (HF) with reduced ejection fraction (NYHA class II-IV). Dapagliflozin has been studied in a wide range of patients with diabetes and plethora of evidence has confirmed its efficacy as a monotherapy as well as an add-on to the oral therapies and insulin, when compared to placebo. Additional advantages include weight reduction which has been consistently demonstrated in Phase III studies and good tolerability. Also there is a demonstrable reduction in systolic blood pressure in patients treated with SGLT2 inhibitors. DECLARE TIMI 58 study clearly demonstrated that Dapagliflozin was non inferior in reducing major adverse cardiovascular events (MACE) in patients with T2DM and high CV risk compared with placebo. 27% risk reduction in heart failure hospitalisation was noted along without increased risk of amputation. DAPA HF evaluated the efficacy and safety of the dapagliflozin in patients with HF and reduced ejection fraction, irrespective of the presence or absence of diabetes. Patients with symptomatic HF due to reduced ejection fraction treated with dapagliflozin had positive outcomes with reduction in cardiovascular deaths and HF events. The DAPA-CKD trial which was conducted to assess the efficacy and safety of dapagliflozin in patients with chronic kidney disease (CKD), with or without type 2 diabetes found that it significantly lowered the risk of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes in patients with CKD, regardless of the presence or absence of diabetes. Ongoing trials like DELIVER, DAPA ACT HF-TIMI 68, DICTATE-AHF, HF readmission study, DAPA MI Study, Effectiveness of Dapagliflozin for Weight Loss, will throw more light on the precise effects of dapagliflozin in several clinical scenarios. To conclude - Dapagliflozin was well studied not only in T2DM but also in HF and CKD patients with positive results and good safety profile.

Clinical Evidence of Evogliptin plus Metformin in Management of Type 2 Diabetes mellitus.

Achieving adequate glycemic control in type 2 diabetes mellitus (T2DM) remains a difficult but achievable goal. Oral agents (OADs) are important option for management of T2DM. Most T2DM patients require more than one medication for adequate glycemic control. Metformin based combination therapy is recommended when monotherapy is insufficient. Evogliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which can to be combined with metformin for treating T2DM. Combination therapy of Evogliptin and Metformin lowers blood glucose via augmentation of insulin secretion, suppression of glucagon secretion, and insulin sensitization. Co-administration of Evogliptin and Metformin showed no clinically relevant pharmacokinetic differences compared to the administration of each drug alone. Combination therapy of Evogliptin and Metformin also provides significantly better glycemic control compared to the respective monotherapies. Efficacy and safety of Evogliptin and Metformin had been demonstrated in several multicentre randomized clinical trials conducted in various countries like South Korea, Russia and India. Consequently, fixed dose combination (FDC) of Evogliptin and Metformin is approved in South Korea and India. Complexity of the treatment regimen and polypharmacy are well-known factors of poor medication adherence and FDCs have the potential to improve adherence by reducing the pill burden. Adoption of this combination therapy in clinical practice for management of T2DMs will provide a greater degree of HbA1c reduction than that observed with the use of either drug as monotherapy, and is unlikely to cause significant hypoglycemia. Combination therapy of Evogliptin and Metformin is a promising strategy in the treatment of T2DM.

Efficacy and safety of evogliptin versus sitagliptin as an add-on therapy in Indian patients with type 2 diabetes mellitus inadequately controlled with metformin: A 24-week randomized, double-blind, non-inferiority, EVOLUTION INDIA study.

AIM: This study aimed to assess efficacy and safety of evogliptin versus sitagliptin, when added to background metformin therapy in Indian patients with uncontrolled type 2 diabetes. METHOD: Overall, 184 patients with uncontrolled type 2 diabetes (7% ≤ HbA1c < 10%) receiving ≥8 weeks of stable metformin monotherapy (≥1 g/day), were randomized to receive add-on treatment (evogliptin 5 mg or sitagliptin 100 mg) for 24 weeks. Primary endpoint was change in HbA1c from baseline to 12 weeks (non-inferiority margin: <0.35). RESULTS: Mean reductions in HbA1c at 12 weeks in evogliptin- and sitagliptin-treated patients were -0.37 (1.06) and -0.32 (1.14), respectively. The adjusted mean difference between treatment groups was -0.022 (95% CI: -0.374, 0.330; P = 0.901), that demonstrated non-inferiority. Reductions in FPG and PPG were similar between evogliptin and sitagliptin at 12 and 24 weeks. Changes in body weight were comparable between the treatment groups. Patients achieving target HbA1c < 7.0% (evogliptin, 26.7% vs. sitagliptin, 20%) was almost equal in both groups. Treatment-emergent adverse events occured in 52 patients (evogliptin, 25% and sitagliptin, 31.5%) and were generally mild. CONCLUSIONS: Evogliptin was non-inferior to sitagliptin in HbA1c reduction. It effectively improved glycemic control and was well tolerated in type 2 diabetes patients inadequately controlled by metformin alone.

Arbekacin - A Novel Antibiotic for Critical Infections.

Antibiotic resistance is one of the biggest menace to global health. Deaths from Drug-resistant infections is set to escalate exponentially. Pipeline for new antibacterials is almost empty. The World Health Organization has reinforced its warning that to tackle growing threat of antimicrobial resistance, development of a new antibiotics is seriously lacking. Arbekacin is a novel aminoglycoside primarily used in the treatment of infections caused by resistant Staphylococcus Aureus i.e. Methicillin Resistant Staphylococcus Aureus (MRSA). Besides MRSA it also demonstrates activity against Enterococci and several Gram negative pathogens such as Klebsiella pneumonia, Pseudomonas aeruginosa, Acinetobacter baumannii including resistant strain. Arbekacin which has been used in Japan and Korea since more than two and half decades has been recently approved in India. This review will examine how Arbekacin evades the common mechanisms of antibiotic resistance, the pharmacokinetics of Arbekacin, and the various pharmacological properties and its spectrum of in vitro activity. The results of clinical trials on Arbekacin are also described, as is the patient safety and tolerability observed during these studies.

Dabigatran - the First Approved DTI for SPAF.

Atrial fibrillation (AF) is commonly occurring arrhythmia in clinical practice. AF is easy to recognize but difficult to treat. Stroke is the most devastating complication of AF and is associated with a huge disease burden on the society. Effective stroke prevention is a priority for patients with AF. Two-thirds of strokes due to AF are preventable with suitable anticoagulant therapy. VKA like warfarin, acenocoumarol remains the gold standard for stroke prevention in AF (SPAF). However, it is associated with numerous limitations such as a high risk of drug-drug, drug-food interactions and need for frequent PT/INR monitoring. Dabigatran etexilate is a selective, specific, reversible direct thrombin inhibitor that has been approved in United States, European countries and in India for SPAF and primary venous thromboembolism prevention and treatment. The efficacy and safety of dabigatran in AF has been established the "Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY)", a randomized clinical trial. As per RE-LY trial 150-mg dose of dabigatran was superior to warfarin with respect to stroke or systemic embolism, and the 110-mg dose was superior to warfarin with respect to major bleeding. The adverse event profile of dabigatran etexilate was generally similar to that of warfarin in the RE-LY study, except for the incidence of dyspepsia. Dabigatran has edge over VKAs like warfarin and acenocoumarol including predictable pharmacokinetic and pharmacodynamic profile, minimal drug-drug and no drug-food interactions while no monitoring is needed. Dosing schedule is dabigatran 150mg BID patients with normal renal function. 110 mg BID is specifically for elderly patients above 80 years and over, as well as for patients at an increased risk of bleeding and in renal impairment CrCL 15-30 mL/min dosing is 75mg twice daily. Dabigatran is only NOAC with approved specific reversal agent.

DemographIc Assessment and EValuation of DEgree of Lipid Control in High Risk Indian DySlipidemia PatiEnts (DIVERSE Study).

BACKGROUND: Cardiovascular diseases (CVD's) are the major cause of morbidity and mortality in both developed and developing countries. Many clinical trials have demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering, reduces the incidence of coronary and cerebrovascular events across a broad spectrum of patients at risk. Guidelines for the management of patients at risk have been established in Europe and North America. The guidelines have advocated progressively lower LDL-C targets and more aggressive use of statin therapy. In Indian patients, comprehensive data on dyslipidemia management and its treatment outcomes are inadequate. There is lack of information on existing treatment patterns, the patient's profile being treated, and factors that determine treatment success or failure in achieving desired goals. PURPOSE: The present study was planned to determine the lipid control status in high-risk dyslipidemic patients treated with lipid-lowering therapy in India. METHODS: This cross-sectional, non-interventional, single visit program was conducted across 483 sites in India where male and female patients with high-risk dyslipidemia aged 18 to 65 years who had visited for a routine health check-up to their respective physician at hospital or a healthcare center. Percentage of high-risk dyslipidemic patients achieving adequate LDL-C level (< 70 mg/dL) on lipid-lowering therapy and the association of lipid parameters with patient characteristics, comorbid conditions, and lipid lowering drugs were analysed. RESULTS: 3089 patients were enrolled in the study; of which 64% were males. LDL-C data was available for 95.2% of the patients; only 7.7% of these patients achieved LDL-C levels < 70 mg/dL on lipid-lowering therapy, which may be due to inability to follow therapeutic plans, poor compliance, or inadequate counselling by physician. The physician's lack of awareness about recent treatment guidelines also might contribute to patients' poor adherence, not explaining adequately the benefit and risks of a medication, not giving consideration to the patient's life style and the cost of medication. Statin was the most commonly used anti-dyslipidemic drug across population. The higher proportion of patients had the comorbid condition of CVD and diabetes mellitus across all dyslipidemic patients. CONCLUSIONS: As per the European Society of Cardiology guidelines the ideal LDL-C levels in high risk dyslipidemic patients should be less than 70 mg/dL. In the present study, 7.7% of the patients achieved LDL-C levels < 70 mg/dL on lipid lowering therapy which is very less. Most of high risk dyslipidemic patients in India are on suboptimal dosage of statin. So more aggressive and high dosage statin therapy may be required to achieve target LDLC levels in high risk Indian dyslipidemic patients.

Management Practices in Indian Patients with Uncontrolled Hypertension.

INTRODUCTION: Hypertension (HTN), being a major risk factor for cardiovascular diseases (CVDs), is an important issue of medical and public health. High blood pressure (BP) is ranked as the third most important risk factor for attributable burden of disease in south Asia (2010). Hypertension (HTN) exerts a substantial public health burden on cardiovascular health status and healthcare systems in India. Uncontrolled hypertension among adults with hypertension is associated with increased mortality. An inadequate data is available in India on uncontrolled hypertension. OBJECTIVES: The present study was planned to evaluate the patient profile, co-morbidities, management in uncontrolled hypertensive patients and also to determine the number of patients with resistant hypertension across India. METHODS: A total of 4725 uncontrolled hypertensive patients who were on anti-hypertensive medications were evaluated in this cross-sectional and observational study. The observed patterns were recorded with respect to the prevalence of uncontrolled hypertension and evaluate the socio-demographic, medical history, anthropometric variables and treatment preferences in Indian patients with uncontrolled hypertension. RESULTS: Majority of the patients with uncontrolled hypertension were males (71.4%) and aged 46-65 years. Most of the study population were pre-obese (males: 35.7%; females: 27.4%). Higher proportion of patients with uncontrolled hypertension were residents of Maharashtra (25.6%) and Gujarat (11.6%). Antihypertensive monotherapy was used by 45.4% and 54.6% patients used combination therapy (≥ 2 categories of anti-hypertensive medications). Angiotensin receptor blockers (ARBs) were the most preferred agent as monotherapy (70.6%) and also the most common component of dual and triple combination anti-hypertensive agent. 19.5% (922/4725) patients had resistant hypertension and 80% of the patients were aged 46-65 years. Higher proportion of patients were males (67.2%; 620/922) and higher proportion of patients were to residents of Andhra Pradesh (21.4% patients) and Maharashtra (19.3% patients). All 922 resistant hypertensive patients were on ≥ 3 anti-hypertensive medications and received ARB + CCB + Diuretics as the most preferred anti-hypertensive combination therapy. Diabetes and dyslipidaemia were the major comorbidities reported in patients with uncontrolled and resistant hypertension. Lipid lowering agents followed by oral hypoglycaemic agents and antiplatelet medications were the common concomitant medications used. Various factor responsible for not achieving the desired blood pressure goals may be the physician's lack of awareness about recent hypertensive treatment guidelines that might contribute to patient's poor adherence due to not explaining adequately the benefit and risks of a medication, not giving consideration to the patient's life style, the cost of medication, and inadequate dose titration. CONCLUSIONS: Uncontrolled hypertension is a major problem in India. It is prudent to focus on multiple risk factors while treating hypertension. A combination therapy with multiple blood pressure lowering drugs are important and concerns should be identified while selecting the appropriate dosage of combinations of anti-hypertensive therapy and adherence to the therapy. The preferred choices for mono, dual combination and triple combination anti-hypertensive regimens are ARBs; ARB + CCB; ARB + CCB + Diuretics, respectively. In this study, most of the patients were on monotherapy; however a rationale combination therapy or dose adjustment is required for the effective management of hypertension. The protective measures to be taken to control hypertension includes reduction of physicians inertia, diet and physical activity, regular patient follow-up with BP measurements and counselling, and the improvement in patient adherence.

Acenocoumarol: A Review of Anticoagulant Efficacy and Safety.

Anticoagulant treatment is required for the treatment and prevention of thromboembolic disorders. Vitamin K antagonists are commonly used oral anticoagulants worldwide. Acenocoumarol is mono-coumarin derivative with racemic mixture of R (+) and S (-) enantiomers. Efficacy and safety of acenocoumarol has been evaluated in atrial fibrillation, cardiac valve replacement, after myocardial infarction, treatment of deep vein thrombosis, after major surgeries and after critical illness requiring prolonged hospitalization. Acenocoumarol is effective and safe in all age groups. It offers an advantage over warfarin in terms of better stability of anti-coagulant effect. Due to its economic advantage acenocoumarol may be suitable oral anticoagulant for long term use in countries like India.

A Study of salt and fat Consumption pattern in Regional Indian diet among hypertensive and dyslipidemic PaTients - SCRIPT study.

BACKGROUND: Cardiovascular diseases are leading cause of mortality and morbidity. There is an increasing prevalence of hypertension and dyslipidemia due to globalization and adoption of westernized dietary habits in India. These transitions are manifest in dietary patterns and health outcomes. OBJECTIVE: To study the dietary salt and fat intake among patients diagnosed with hypertension and dyslipidemia in India. METHODS: SCRIPT study was a pilot exploratory, cross-sectional, observational, descriptive, multi-center study. It was conducted across hospitals and clinics in five metro cities of India, represented into four regional zones. In each region (North, n = 113; East, n = 98; West, n = 83; South, n = 152), patients diagnosed with hypertension and dyslipidemia were enrolled in the study. Socio-demographic and treatment details were recorded. Participants were interviewed by a dietician and their dietary intake was assessed by a three-day recall of food item questionnaire/ food diary. RESULTS: Overall the mean total daily salt consumption was 10.9 grams. Region-wise, the mean daily salt consumption in North, East, West and South were 14.13, 9.81, 10.12 and 9.38 grams respectively. The daily salt consumption in the North was significantly higher than other regions (P=0.012). The daily consumption of saturated fats (total saturated fat, ghee and butter) in the North was higher and statistically significantly in comparison to West, South and East (P <0.05). Overall, fats contributed to 24.1%, proteins contributed to 12.7% and carbohydrate contributed to 63.2% of total energy per day. The percentage of fat and protein contributing to total energy per day was within the acceptable range. CONCLUSIONS: Our study documented higher dietary salt intake than that recommended in India. There is an urgent need to address the issue of high salt and saturated fat consumption. Nutritional strategies for reducing salt intake, saturated fat and balancing energy nutrients should be urgently applied in Indian hypertensive and dyslipidemia patients.

Fondaparinux in Acute Coronary Syndromes.

Anticoagulant therapy is a major component in the management of acute coronary syndromes (ACS). Anticoagulant-associated adverse events like heparin-induced thrombocytopenia, bleeding complications and need of close monitoring of anticoagulation led to focus on developing agents causing anticoagulation without affecting primary haemostasis. Fondaparinux, a new-age synthetic anticoagulant, acts by inhibiting factor Xa. It is simple to administer and has low inter and intra-subject variability. Moreover, there is no risk of significant drug interactions and no need for monitoring the platelet count. Efficacy of fondaparinux has been studied in various disorders including prevention of venous thromboembolism in major orthopaedic surgery, abdominal surgery and acutely ill medical patients, treatment of venous thromboembolism, non-ST-elevation acute coronary syndromes and ST-elevation acute myocardial infarction. This article covers the review of fondaparinux and its practical advantages mainly in the management of ACS including non-ST-elevation acute coronary syndromes and ST-elevation acute myocardial infarction.