lesinurad in combination with allopurinol a randomised, double blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational clear 2 study)
Lesinurad in combination with allopurinol was superior to allopurinol alone in lowering serum uric acid levels in patients with gout and inadequate response to allopurinol. The study randomized 610 patients taking allopurinol to add either lesinurad 200 mg, lesinurad 400 mg, or placebo daily for 12 months. At month 6, significantly more patients achieved the target serum uric acid level of less than 6.0 mg/dL with lesinurad 200 mg (55.4%) and lesinurad 400 mg (66.5%) compared to allopurinol alone (23.3%). The lesinurad 200 mg dose showed a safety profile
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
This document summarizes a clinical trial that evaluated the safety and efficacy of patiromer for treating hyperkalemia in patients with chronic kidney disease receiving RAAS inhibitors. The trial had two phases - an initial 4-week treatment phase followed by an 8-week randomized withdrawal phase. Results showed that patiromer significantly reduced serum potassium levels and maintained normokalemia compared to placebo. The most common side effects were constipation and diarrhea. The authors concluded that patiromer was effective for treating hyperkalemia and allowing continued use of RAAS inhibitors in patients with chronic kidney disease.
This study investigated the effects of intensive glucose control versus conventional glucose control in critically ill patients admitted to the ICU. Over 6000 patients were randomly assigned to either a tight glucose control target of 81-108 mg/dL or a more conventional target of 180 mg/dL or less. The primary outcome was all-cause mortality within 90 days. Results showed that intensive glucose control was associated with a higher mortality rate compared to conventional control, with 27.5% of patients in the intensive group dying compared to 24.9% in the conventional group. Intensive control also significantly increased the risk of severe hypoglycemia.
The biomarker of choice in association of dyslipidemia with osteoporosis: A c...SriramNagarajan17
This case study describes a 55-year-old male patient who presented with pain in his lower limb and was diagnosed with both dyslipidemia and osteoporosis based on his medical history and laboratory tests. He had a family history of metabolic diseases and consumed excessive alcohol. His dyslipidemia was diagnosed based on genetic predisposition and lipid profile showing low HDL and high LDL levels. His osteoporosis was diagnosed a year and a half later when he fractured his femur during a walk and was found to have low bone mineral density. The conclusion is that low HDL and high LDL levels in the lipid profile are the biomarker of choice for associating dyslipidemia with osteoporosis as these
This study investigated whether treatment with the proton pump inhibitor lansoprazole could reduce the frequency of common colds and exacerbations in patients with chronic obstructive pulmonary disease (COPD). The study found that patients taking lansoprazole had significantly fewer COPD exacerbations and a lower risk of frequent common colds compared to the control group. The results suggest that lansoprazole may help reduce airway inflammation and inhibit rhinovirus infection in COPD patients. However, the study was limited by a small sample size, lack of placebo control, and population that was almost entirely male and of Japanese ethnicity.
This document summarizes a drug use evaluation (DUE) of daptomycin from June to October 2014. Data was collected from 21 patients on daptomycin, but 10 patients were excluded for reasons such as duplication, not completing therapy, or having an actual body weight less than 130% of ideal body weight. The remaining 10 patients were included in the analysis. Most patients were dosed using adjusted body weight and had indications of MRSA infections or reactions to vancomycin. Adverse reactions occurred in 2 patients. Outcomes included resolution of infection in 5 patients, discontinuation due to adverse reactions in 2 patients, and discontinuation due to lack of efficacy in 3 patients. The study had a small sample size making it
This study investigated calcium and vitamin D intake in healthy children. 184 children with intake below recommendations were randomly assigned to receive dietary counseling plus calcium/vitamin D supplements (Group 1) or counseling alone (Group 2). After 4 months, Group 1 showed improved intake of both nutrients and optimal vitamin D levels, while Group 2 only improved calcium intake and had lower vitamin D levels. The study concludes that counseling alone is not sufficient to achieve adequate vitamin D intake.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
This document summarizes a clinical trial that evaluated the safety and efficacy of patiromer for treating hyperkalemia in patients with chronic kidney disease receiving RAAS inhibitors. The trial had two phases - an initial 4-week treatment phase followed by an 8-week randomized withdrawal phase. Results showed that patiromer significantly reduced serum potassium levels and maintained normokalemia compared to placebo. The most common side effects were constipation and diarrhea. The authors concluded that patiromer was effective for treating hyperkalemia and allowing continued use of RAAS inhibitors in patients with chronic kidney disease.
This study investigated the effects of intensive glucose control versus conventional glucose control in critically ill patients admitted to the ICU. Over 6000 patients were randomly assigned to either a tight glucose control target of 81-108 mg/dL or a more conventional target of 180 mg/dL or less. The primary outcome was all-cause mortality within 90 days. Results showed that intensive glucose control was associated with a higher mortality rate compared to conventional control, with 27.5% of patients in the intensive group dying compared to 24.9% in the conventional group. Intensive control also significantly increased the risk of severe hypoglycemia.
The biomarker of choice in association of dyslipidemia with osteoporosis: A c...SriramNagarajan17
This case study describes a 55-year-old male patient who presented with pain in his lower limb and was diagnosed with both dyslipidemia and osteoporosis based on his medical history and laboratory tests. He had a family history of metabolic diseases and consumed excessive alcohol. His dyslipidemia was diagnosed based on genetic predisposition and lipid profile showing low HDL and high LDL levels. His osteoporosis was diagnosed a year and a half later when he fractured his femur during a walk and was found to have low bone mineral density. The conclusion is that low HDL and high LDL levels in the lipid profile are the biomarker of choice for associating dyslipidemia with osteoporosis as these
This study investigated whether treatment with the proton pump inhibitor lansoprazole could reduce the frequency of common colds and exacerbations in patients with chronic obstructive pulmonary disease (COPD). The study found that patients taking lansoprazole had significantly fewer COPD exacerbations and a lower risk of frequent common colds compared to the control group. The results suggest that lansoprazole may help reduce airway inflammation and inhibit rhinovirus infection in COPD patients. However, the study was limited by a small sample size, lack of placebo control, and population that was almost entirely male and of Japanese ethnicity.
This document summarizes a drug use evaluation (DUE) of daptomycin from June to October 2014. Data was collected from 21 patients on daptomycin, but 10 patients were excluded for reasons such as duplication, not completing therapy, or having an actual body weight less than 130% of ideal body weight. The remaining 10 patients were included in the analysis. Most patients were dosed using adjusted body weight and had indications of MRSA infections or reactions to vancomycin. Adverse reactions occurred in 2 patients. Outcomes included resolution of infection in 5 patients, discontinuation due to adverse reactions in 2 patients, and discontinuation due to lack of efficacy in 3 patients. The study had a small sample size making it
This study investigated calcium and vitamin D intake in healthy children. 184 children with intake below recommendations were randomly assigned to receive dietary counseling plus calcium/vitamin D supplements (Group 1) or counseling alone (Group 2). After 4 months, Group 1 showed improved intake of both nutrients and optimal vitamin D levels, while Group 2 only improved calcium intake and had lower vitamin D levels. The study concludes that counseling alone is not sufficient to achieve adequate vitamin D intake.
This randomized controlled trial evaluated glycemic durability of rosiglitazone, metformin, and glyburide monotherapy in patients with recently diagnosed type 2 diabetes over 4 years. The primary outcome was time to treatment failure defined as fasting plasma glucose >180 mg/dL. Rosiglitazone showed a lower risk of treatment failure compared to metformin (32% lower) and glyburide (63% lower). Glyburide was associated with a lower risk of cardiovascular events than rosiglitazone, while metformin had a similar risk profile to rosiglitazone. All drugs showed differing adverse event profiles.
CompAct Renal 2012-2014 - Top 10 Articlespa21vifor
This document provides a summary of 10 articles from the CompAct Renal platform that discuss various topics related to the treatment of hyperphosphatemia and CKD-MBD. The articles cover subjects like the association between phosphate binder use and lower mortality, insights into optimal hyperphosphatemia treatment, causes of non-adherence to treatment regimens, the relationship between high pill burden and disease burden, challenges of implementing renal diets, and novel research on FGF-23 and potential treatment strategies. The document is a compilation of CompAct's most read articles from the past two years on issues surrounding hyperphosphatemia management and CKD-MBD.
Ibalizumab - Journal Club Handout (Holden Young - Roseman University of Healt...HoldenYoung3
This phase 3 study evaluated the efficacy and safety of ibalizumab in treating 40 patients with multi-drug resistant HIV-1. Ibalizumab is a monoclonal antibody that binds to CD4 receptors to prevent viral entry. At day 14, 83% of patients had at least a 0.5 log10 reduction in viral load from baseline. At week 25, 63% maintained this reduction. The most common adverse event was mild-to-moderate diarrhea in 8 patients. Ibalizumab combined with optimized antiretroviral therapy showed significant antiviral activity against multi-drug resistant HIV-1 strains.
International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases
Basal bolus insulin therapy resulted in improved glycemic control compared to sliding scale insulin therapy for hospitalized patients with type 2 diabetes, according to the RABBIT 2 trial. The mean daily blood glucose was 27 mg/dL lower in patients receiving basal glargine plus prandial glulisine compared to those receiving sliding scale regular insulin. Both regimens resulted in a similar rate of hypoglycemia and length of hospital stay. Basal bolus insulin provided better glycemic control and achieved target blood glucose levels under 140 mg/dL in more patients than sliding scale insulin alone.
This document discusses the increasing use of therapeutic monoclonal antibodies in internal medicine. It provides examples of monoclonal antibodies used in various specialties like hematology/oncology, rheumatology, gastroenterology, and cardiology. The document outlines the historical development of monoclonal antibody technology from the 1890s to modern advances in recombinant DNA and transgenic mice that have allowed for humanized monoclonal antibodies. It notes both the benefits monoclonal antibodies have provided but also the issues of diminishing response, high costs, and sometimes unanticipated safety risks. The document concludes by predicting more monoclonal antibody approvals and emphasizes the need for rigorous evaluation of safety, efficacy and cost-effectiveness as with other medical therapies.
The AFFIRM trial compared rate control and rhythm control strategies for treating atrial fibrillation. Over 7,000 patients with recurrent atrial fibrillation aged 65 or older were randomized to either rate or rhythm control. The primary outcome was overall mortality, with secondary outcomes including death from cardiovascular causes, stroke, bleeding, and hospitalization. The trial found no significant difference in mortality between the two groups. However, rhythm control was associated with greater need for hospitalization and higher rates of crossover to rate control. The study concluded that rate control should be the primary treatment approach for atrial fibrillation.
PEPTIC (Holden Young - Roseman University College of Pharmacy)HoldenYoung3
PEPTIC (Holden Young - Roseman University College of Pharmacy)
Effect of stress ulcer prophylaxis with proton pump inhibitors vs histamine-2 receptor blockers on in-hospital
mortality among ICU patients receiving invasive mechanical ventilation (PEPTIC).
JAMA . 2020; 323(7):616-626
Non-adherence to phosphate binder medication is common among dialysis patients, with studies finding adherence rates between 22-74%. Poor adherence is a major contributor to inadequate control of serum phosphorus levels in over 50% of patients. Several factors influence non-adherence, including high pill burden, complex dosing regimens, poor medication tolerability, and psychosocial factors. Improving adherence could lead to better control of phosphorus levels and potentially improved health outcomes and reduced healthcare costs.
This study investigated the effects of omega-3 fatty acids, vitamin C, and zinc supplementation individually and combined on asthma control in children. 76 children with moderate persistent asthma were randomly assigned to receive normal diet plus placebo, omega-3, zinc, vitamin C, or a combination of all three supplements over 5 phases. Asthma control was assessed using ACT scores, pulmonary function tests, and sputum inflammation markers. The combination phase showed the greatest improvement in ACT scores, lung function, and reduction of inflammatory markers compared to placebo or single supplements. This study suggests children with asthma may benefit from dietary supplementation with omega-3s, vitamin C, and zinc.
This study compared the urate-lowering drug febuxostat to allopurinol in 762 patients with hyperuricemia and gout. Patients received either 80 mg or 120 mg of febuxostat daily or 300 mg of allopurinol daily for 52 weeks. The primary outcome was achieving a serum urate level less than 6.0 mg/dL, which was reached by 53% on 80 mg febuxostat, 62% on 120 mg febuxostat, and 21% on allopurinol. Rates of gout flares and reductions in tophus size were similar between groups. More patients discontinued the 120 mg febuxostat group than the other groups due
The document discusses the role of peroxisome proliferator activated receptor gamma (PPARγ) agonists in treating type 2 diabetes and reducing cardiovascular risk. PPARγ agonists like thiazolidinediones improve insulin sensitivity and have beneficial effects on lipids, inflammation, and vascular cell proliferation. They may reduce cardiovascular events in type 2 diabetes through these metabolic and anti-inflammatory mechanisms. However, PPARγ agonists can also cause side effects like fluid retention, weight gain, and congestive heart failure, so their risks and benefits must be carefully weighed.
This document discusses barriers to insulin therapy. It notes that while diabetes guidelines recommend tight glycemic control through insulin therapy, few patients actually achieve target HbA1c levels. Barriers include limitations among healthcare providers in providing education on proper insulin administration techniques, as well as patient challenges like fear of hypoglycemia, weight gain, and the perceived complexity of insulin treatment. Overcoming these barriers through education on insulin products like Insuman, which can be easily resuspended to ensure accurate dosing, and reusable insulin pens like AllStar, which are easy for patients to use correctly, may help improve adherence to insulin regimens.
This study evaluated the efficacy and safety of lacosamide in treating diabetic neuropathic pain through an 18-week double-blind trial of 370 patients with doses of 200 mg/day, 400 mg/day, and 600 mg/day compared to a placebo. The 400 mg/day dose was found to significantly improve pain scores over the placebo and had the optimal balance of efficacy and side effects. Common side effects included dizziness, tremor and headache. While lacosamide showed potential for treating diabetic neuropathic pain, the study period was short and the 600 mg/day group had a high withdrawal rate due to adverse events.
Journal club presentation: by RxVichuZ!! ;)RxVichuZ
My 97th powerpoint... deals with the comparative study of efficacy of piperacillin-tazobactam, as compared to meropenem in the treatment of ESBL(Extended spectrum beta-lactamases) infections.
A summarized insight has been provided, using research article from JAMA.
This multicenter study evaluated the efficacy and safety of rituximab treatment in 57 patients with difficult-to-treat nephrotic syndrome, including 24 with steroid-dependent nephrotic syndrome (SDNS) and 33 with steroid-resistant nephrotic syndrome (SRNS). At a mean follow-up of 16-21 months, rituximab led to sustained remission in 83% of SDNS patients and 48.5% of SRNS patients. It also significantly reduced relapse rates in SDNS patients. The treatment was generally well-tolerated with few minor infusion-related reactions reported. Larger controlled trials are still needed to confirm rituximab's benefits in nephrotic
This study examined the effects of ezetimibe treatment for 3 months on glucose metabolism in 96 Japanese patients with type 2 diabetes and hypercholesterolemia. Ezetimibe treatment significantly lowered LDL-cholesterol levels. HbA1c levels decreased in approximately 50% of patients after treatment. Univariate analysis found that changes in HbA1c were associated with serum alanine aminotransferase levels, aspartate aminotransferase to alanine aminotransferase ratio, and age. Higher baseline ALT levels and an AST/ALT ratio below 1.0 were significantly associated with decreases in HbA1c following ezetimibe administration, suggesting ezetimibe may improve glucose control through effects on
Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
Statin use was associated with a statistically significant increased risk of developing diabetes in postmenopausal women according to a study using data from the Women's Health Initiative. The risk was found across all subgroups tested and persisted even after adjusting for potential confounding factors. However, the study did not prove causation and a subset analysis using fasting glucose did not replicate the increased risk finding. The authors conclude statins have cardiovascular benefits but more research is needed to establish if they causally increase diabetes risk.
This document summarizes a clinical trial that compared the uric acid lowering efficacy and safety of febuxostat to allopurinol in treating hyperuricemia in gout patients. The trial found that febuxostat 80mg daily was more effective at lowering uric acid levels than either febuxostat 40mg or allopurinol 300/200mg, especially in patients with mild to moderate kidney impairment. Febuxostat 40mg and allopurinol 300/200mg showed equivalent uric acid lowering efficacy. The safety profiles of febuxostat and allopurinol were found to be comparable.
Mitapivat is an oral activator of pyruvate kinase that has shown promise in treating pyruvate kinase deficiency and other hemolytic anemias. Clinical trials have found it to be well-tolerated and able to significantly increase hemoglobin levels in patients with pyruvate kinase deficiency or thalassemia. Ongoing phase 2 and 3 trials are investigating its efficacy and safety for reducing transfusions in thalassemia and decreasing symptoms in sickle cell disease.
This randomized controlled trial evaluated glycemic durability of rosiglitazone, metformin, and glyburide monotherapy in patients with recently diagnosed type 2 diabetes over 4 years. The primary outcome was time to treatment failure defined as fasting plasma glucose >180 mg/dL. Rosiglitazone showed a lower risk of treatment failure compared to metformin (32% lower) and glyburide (63% lower). Glyburide was associated with a lower risk of cardiovascular events than rosiglitazone, while metformin had a similar risk profile to rosiglitazone. All drugs showed differing adverse event profiles.
CompAct Renal 2012-2014 - Top 10 Articlespa21vifor
This document provides a summary of 10 articles from the CompAct Renal platform that discuss various topics related to the treatment of hyperphosphatemia and CKD-MBD. The articles cover subjects like the association between phosphate binder use and lower mortality, insights into optimal hyperphosphatemia treatment, causes of non-adherence to treatment regimens, the relationship between high pill burden and disease burden, challenges of implementing renal diets, and novel research on FGF-23 and potential treatment strategies. The document is a compilation of CompAct's most read articles from the past two years on issues surrounding hyperphosphatemia management and CKD-MBD.
Ibalizumab - Journal Club Handout (Holden Young - Roseman University of Healt...HoldenYoung3
This phase 3 study evaluated the efficacy and safety of ibalizumab in treating 40 patients with multi-drug resistant HIV-1. Ibalizumab is a monoclonal antibody that binds to CD4 receptors to prevent viral entry. At day 14, 83% of patients had at least a 0.5 log10 reduction in viral load from baseline. At week 25, 63% maintained this reduction. The most common adverse event was mild-to-moderate diarrhea in 8 patients. Ibalizumab combined with optimized antiretroviral therapy showed significant antiviral activity against multi-drug resistant HIV-1 strains.
International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases
Basal bolus insulin therapy resulted in improved glycemic control compared to sliding scale insulin therapy for hospitalized patients with type 2 diabetes, according to the RABBIT 2 trial. The mean daily blood glucose was 27 mg/dL lower in patients receiving basal glargine plus prandial glulisine compared to those receiving sliding scale regular insulin. Both regimens resulted in a similar rate of hypoglycemia and length of hospital stay. Basal bolus insulin provided better glycemic control and achieved target blood glucose levels under 140 mg/dL in more patients than sliding scale insulin alone.
This document discusses the increasing use of therapeutic monoclonal antibodies in internal medicine. It provides examples of monoclonal antibodies used in various specialties like hematology/oncology, rheumatology, gastroenterology, and cardiology. The document outlines the historical development of monoclonal antibody technology from the 1890s to modern advances in recombinant DNA and transgenic mice that have allowed for humanized monoclonal antibodies. It notes both the benefits monoclonal antibodies have provided but also the issues of diminishing response, high costs, and sometimes unanticipated safety risks. The document concludes by predicting more monoclonal antibody approvals and emphasizes the need for rigorous evaluation of safety, efficacy and cost-effectiveness as with other medical therapies.
The AFFIRM trial compared rate control and rhythm control strategies for treating atrial fibrillation. Over 7,000 patients with recurrent atrial fibrillation aged 65 or older were randomized to either rate or rhythm control. The primary outcome was overall mortality, with secondary outcomes including death from cardiovascular causes, stroke, bleeding, and hospitalization. The trial found no significant difference in mortality between the two groups. However, rhythm control was associated with greater need for hospitalization and higher rates of crossover to rate control. The study concluded that rate control should be the primary treatment approach for atrial fibrillation.
PEPTIC (Holden Young - Roseman University College of Pharmacy)HoldenYoung3
PEPTIC (Holden Young - Roseman University College of Pharmacy)
Effect of stress ulcer prophylaxis with proton pump inhibitors vs histamine-2 receptor blockers on in-hospital
mortality among ICU patients receiving invasive mechanical ventilation (PEPTIC).
JAMA . 2020; 323(7):616-626
Non-adherence to phosphate binder medication is common among dialysis patients, with studies finding adherence rates between 22-74%. Poor adherence is a major contributor to inadequate control of serum phosphorus levels in over 50% of patients. Several factors influence non-adherence, including high pill burden, complex dosing regimens, poor medication tolerability, and psychosocial factors. Improving adherence could lead to better control of phosphorus levels and potentially improved health outcomes and reduced healthcare costs.
This study investigated the effects of omega-3 fatty acids, vitamin C, and zinc supplementation individually and combined on asthma control in children. 76 children with moderate persistent asthma were randomly assigned to receive normal diet plus placebo, omega-3, zinc, vitamin C, or a combination of all three supplements over 5 phases. Asthma control was assessed using ACT scores, pulmonary function tests, and sputum inflammation markers. The combination phase showed the greatest improvement in ACT scores, lung function, and reduction of inflammatory markers compared to placebo or single supplements. This study suggests children with asthma may benefit from dietary supplementation with omega-3s, vitamin C, and zinc.
This study compared the urate-lowering drug febuxostat to allopurinol in 762 patients with hyperuricemia and gout. Patients received either 80 mg or 120 mg of febuxostat daily or 300 mg of allopurinol daily for 52 weeks. The primary outcome was achieving a serum urate level less than 6.0 mg/dL, which was reached by 53% on 80 mg febuxostat, 62% on 120 mg febuxostat, and 21% on allopurinol. Rates of gout flares and reductions in tophus size were similar between groups. More patients discontinued the 120 mg febuxostat group than the other groups due
The document discusses the role of peroxisome proliferator activated receptor gamma (PPARγ) agonists in treating type 2 diabetes and reducing cardiovascular risk. PPARγ agonists like thiazolidinediones improve insulin sensitivity and have beneficial effects on lipids, inflammation, and vascular cell proliferation. They may reduce cardiovascular events in type 2 diabetes through these metabolic and anti-inflammatory mechanisms. However, PPARγ agonists can also cause side effects like fluid retention, weight gain, and congestive heart failure, so their risks and benefits must be carefully weighed.
This document discusses barriers to insulin therapy. It notes that while diabetes guidelines recommend tight glycemic control through insulin therapy, few patients actually achieve target HbA1c levels. Barriers include limitations among healthcare providers in providing education on proper insulin administration techniques, as well as patient challenges like fear of hypoglycemia, weight gain, and the perceived complexity of insulin treatment. Overcoming these barriers through education on insulin products like Insuman, which can be easily resuspended to ensure accurate dosing, and reusable insulin pens like AllStar, which are easy for patients to use correctly, may help improve adherence to insulin regimens.
This study evaluated the efficacy and safety of lacosamide in treating diabetic neuropathic pain through an 18-week double-blind trial of 370 patients with doses of 200 mg/day, 400 mg/day, and 600 mg/day compared to a placebo. The 400 mg/day dose was found to significantly improve pain scores over the placebo and had the optimal balance of efficacy and side effects. Common side effects included dizziness, tremor and headache. While lacosamide showed potential for treating diabetic neuropathic pain, the study period was short and the 600 mg/day group had a high withdrawal rate due to adverse events.
Journal club presentation: by RxVichuZ!! ;)RxVichuZ
My 97th powerpoint... deals with the comparative study of efficacy of piperacillin-tazobactam, as compared to meropenem in the treatment of ESBL(Extended spectrum beta-lactamases) infections.
A summarized insight has been provided, using research article from JAMA.
This multicenter study evaluated the efficacy and safety of rituximab treatment in 57 patients with difficult-to-treat nephrotic syndrome, including 24 with steroid-dependent nephrotic syndrome (SDNS) and 33 with steroid-resistant nephrotic syndrome (SRNS). At a mean follow-up of 16-21 months, rituximab led to sustained remission in 83% of SDNS patients and 48.5% of SRNS patients. It also significantly reduced relapse rates in SDNS patients. The treatment was generally well-tolerated with few minor infusion-related reactions reported. Larger controlled trials are still needed to confirm rituximab's benefits in nephrotic
This study examined the effects of ezetimibe treatment for 3 months on glucose metabolism in 96 Japanese patients with type 2 diabetes and hypercholesterolemia. Ezetimibe treatment significantly lowered LDL-cholesterol levels. HbA1c levels decreased in approximately 50% of patients after treatment. Univariate analysis found that changes in HbA1c were associated with serum alanine aminotransferase levels, aspartate aminotransferase to alanine aminotransferase ratio, and age. Higher baseline ALT levels and an AST/ALT ratio below 1.0 were significantly associated with decreases in HbA1c following ezetimibe administration, suggesting ezetimibe may improve glucose control through effects on
Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
Statin use was associated with a statistically significant increased risk of developing diabetes in postmenopausal women according to a study using data from the Women's Health Initiative. The risk was found across all subgroups tested and persisted even after adjusting for potential confounding factors. However, the study did not prove causation and a subset analysis using fasting glucose did not replicate the increased risk finding. The authors conclude statins have cardiovascular benefits but more research is needed to establish if they causally increase diabetes risk.
Similar to lesinurad in combination with allopurinol a randomised, double blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational clear 2 study)
This document summarizes a clinical trial that compared the uric acid lowering efficacy and safety of febuxostat to allopurinol in treating hyperuricemia in gout patients. The trial found that febuxostat 80mg daily was more effective at lowering uric acid levels than either febuxostat 40mg or allopurinol 300/200mg, especially in patients with mild to moderate kidney impairment. Febuxostat 40mg and allopurinol 300/200mg showed equivalent uric acid lowering efficacy. The safety profiles of febuxostat and allopurinol were found to be comparable.
Mitapivat is an oral activator of pyruvate kinase that has shown promise in treating pyruvate kinase deficiency and other hemolytic anemias. Clinical trials have found it to be well-tolerated and able to significantly increase hemoglobin levels in patients with pyruvate kinase deficiency or thalassemia. Ongoing phase 2 and 3 trials are investigating its efficacy and safety for reducing transfusions in thalassemia and decreasing symptoms in sickle cell disease.
This document summarizes evidence for the efficacy of herbal supplements in treating common chronic conditions such as hypertension, hyperlipidemia, arthritis, and cancer. It finds:
1) Level 1 evidence supports the use of garlic preparations and Hibiscus sabdariffa for lowering blood pressure in hypertension.
2) Garlic and red yeast rice have Level 1 evidence for lowering cholesterol and lipids in hyperlipidemia.
3) Devil's claw, willow bark, turmeric, and boswellia show some evidence (Levels 1-3) for relieving arthritis pain, though more research is still needed.
4) Most oncology experts advise against herbal supplements during cancer treatment due
This document summarizes the results of a randomized, prospective, open-label clinical trial evaluating the efficacy and safety of Sulfad tablets for the management of non-alcoholic steatohepatitis (NASH) patients. The trial involved 100 patients taking Sulfad tablets for 3 months. Significant improvements were seen in liver enzymes and lipid profiles after 1, 2, and 3 months of treatment. No major safety issues were reported. The study concluded that Sulfad tablets were well-tolerated and effective for the management of NASH patients.
efficacy and safety of Sulfad tablets in the management of NASH
patients: A randomized ,prospective, open label, multi-center,
controlled, phase III clinical trial.
This study tested whether treating anemia in patients with type 2 diabetes and chronic kidney disease using darbepoetin alfa would reduce rates of death and cardiovascular events compared to a placebo. Over 4,000 patients were randomized to receive darbepoetin alfa or placebo, with the goal of maintaining a hemoglobin level of 13.0 g/dL in the treatment group. The study found no significant difference in rates of death, cardiovascular events, or end-stage renal disease between the groups. However, there was an increase in stroke risk observed with darbepoetin alfa treatment.
This summary outlines the key findings of the EMPA-KIDNEY trial which evaluated the effect of empagliflozin treatment on kidney disease progression and cardiovascular outcomes in patients with chronic kidney disease (CKD). The randomized, double-blind trial involved over 6,600 patients with CKD across 8 countries. Patients received either empagliflozin 10mg or placebo daily. The primary outcome of kidney disease progression or cardiovascular death occurred in 13.1% of the empagliflozin group versus 16.9% of the placebo group, representing a 28% lower risk with empagliflozin. Secondary outcomes also favored empagliflozin treatment, including lower rates of hospitalization. The benefits were
APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING.docxfestockton
APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING 175CJON.ONS.ORG
C
Nephrotoxicity
Evidence in patients receiving cisplatin therapy
Elizabeth A. Duffy, DNP, RN, CPNP, Wendy Fitzgerald, RN, MSN, PPCNP-BC, CPON®, Kelley Boyle, MSN, RN, PCNS-BC, and Radha Rohatgi, PharmD, BCOP
CISPLATIN IS A PLATINUM COMPOUND THAT HAS BEEN USED as a chemotherapeutic
agent for many different cancers, including ovarian, testicular, lung, cervical,
and bladder cancers (Ruggiero, Rizzo, Trombatore, Maurizi, & Riccardi, 2016;
Santoso, Lucci, Coleman, Shafer, & Hannigan, 2003). The primary dose-
limiting toxicity of cisplatin is nephrotoxicity, a well-known side effect
(Jones, Spunt, Green, & Springate, 2008; Miller, Tadagavadi, Ramesh, &
Reeves, 2010). Nephrotoxicity involves glomerular or tubular dysfunction
of the kidneys after exposure to medications, other treatments, or toxins
(Skinner, 2011). Nephrotoxicity associated with cisplatin is related to accu-
mulation of metabolites in the renal proximal tubule cells of the kidneys,
where about 90% of cisplatin undergoes urinary excretion (Ruggiero et al.,
2016). Accumulation of these metabolites causes direct inflammation; the
production of reactive oxygen species, which leads to oxidative cell damage;
and cell death (Miller et al., 2010; Ruggiero et al., 2016). Many methods are
available to measure kidney function and define nephrotoxicity or acute
kidney injury (see Table 1).
Most patients receiving cisplatin experience acute impairment of glo-
merular and tubular function in varying degrees. Toxicity is dependent on
individual cisplatin pharmacokinetics and is usually more severe with high
total cisplatin doses and when other potential nephrotoxic medications are
given concurrently (Skinner, 2011; Womer, Pritchard, & Barratt, 1985). In one
study, children aged 10 years or older at treatment had a lower glomerular
filtration rate 10 years after therapy compared to children aged younger than
10 years at treatment (Skinner et al., 2009).
Nephrotoxicity can be reversible, but for some individuals, it can result
in permanent kidney injury, chronic progressive renal failure, or renal tubule
function impairment (Skinner et al., 2009). Chronic and severe reductions
of renal function have several sequelae. The immediate impact may be dose
reduction or cessation of potentially lifesaving nephrotoxic chemotherapy,
thereby increasing the risk of relapse or progression of the cancer. In the
event of a disease relapse or progression, changes to renal function may limit
enrollment in phase 1 or 2 clinical trials because of inclusion parameters
related to baseline renal function.
Hydration and diuretics have been used in conjunction with cisplatin
administration for decades to improve the excretion of cisplatin and reduce
the incidence of nephrotoxicity. One method of promoting this excretion is
through osmotic diuresis with mannitol (Morgan et al., 2014). However, the
amount ...
Tirzepatide versus Semiglutide Once Weekly in Patients with Type 2 Diabetes.pdfHaramaya University
This randomized controlled trial compared the efficacy and safety of three doses of tirzepatide (5 mg, 10 mg, and 15 mg), a dual GLP-1 and GIP receptor agonist, to semaglutide (1 mg), a GLP-1 receptor agonist, in 1879 patients with type 2 diabetes inadequately controlled with metformin alone. The primary outcome was the change in HbA1c from baseline to 40 weeks. Key secondary outcomes included changes in body weight and achievement of HbA1c targets. Tirzepatide at all doses resulted in greater reductions in HbA1c and body weight compared to semaglutide and was found to be noninferior and
New class of therapeutic agents called soluble guanylate cyclase (sGC) stimulators.
Impairment of NO synthesis and signaling through the NO-sGC–cGMP pathway is involved in the pathogenesis of pulmonary hypertension.
Dual mode of action,
Directly stimulating sGC independently of NO, and
Increasing the sensitivity of sGC to NO.
vasorelaxation , antiproliferative and antifibrotic effects
Currently efficacy of therapy of patients with
MDR ТВ does not exceed 48.7% worldwide and in Russian
Federation. One of the reason is a frequent development of
adverse drug reactions during the use of combination of
antituberculosis drugs. Since 2013 after registration of
tioureidoiminomethylpyridinium perchlorate (Pecrhlozon®) in
Russian Federation, opportunities appeared for further study
of its efficacy and safety in treatment of tuberculosis with
multiple drug resistance (MDR). In the present study we
applied monitoring of adverse drug reactions during complex
therapy by Perchlozon in combination with five other drugs
with the use of international 5-grade scale. We used Common
Terminology Criteria for Adverse Events (version 3.0). In the
study only mild (grade 1) and moderate (grade 2) adverse drug
reactions were observed except single case when severe (grade
3) adverse drug reaction happened. Mild adverse reactions that
during receiving Perchlozon therapy in complex with other
drugs for MDR-TB did not require its cessation.
Delamanid for multidrug resistant pulmonary tuberculosisHaroon Rashid
Delamanid is a new drug that inhibits mycolic acid synthesis in Mycobacterium tuberculosis. This randomized controlled trial evaluated the safety and efficacy of Delamanid (100 mg or 200 mg twice daily) plus background regimen compared to placebo plus background regimen in 481 patients with multidrug-resistant pulmonary tuberculosis over 2 months. Patients receiving Delamanid had higher rates of sputum culture conversion at 2 months compared to placebo, indicating Delamanid enhances treatment options for multidrug-resistant tuberculosis. However, the short 2-month treatment period was a limitation.
Obesity and hyperlipidemia is international /worldwide problem causing heart disease leading to major predisposing factor for morbidity and death. Conventional medicine used in allopathy include statins, fibrates, niacin and resins but are going to defame due to their adverse effects. Herbal medicine ginger has proved itself as one of the potent anti hyperlipidemic and anti obesity herb with least adverse effects. We did try to compare its hypolipidemic effects with placebo effects when used in mild to moderate hyperlipidemic patients. It was placebo-controlled single blind research study. Research was conducted at National hospital, Lahore, from July to November 2016. Consent was taken from sixty hyperlipidemic patients age range from 25 to 60 years. Both gender male and female patients were enrolled. Patients were randomly divided in two groups, 30 patients were on drug ginger pasted-powder advised to take 5 grams in divided doses with their normal diet for the period of three months. Thirty patients were on placebo pasted-wheat powder, with same color as of ginger powder, advised to take 5 grams in divided doses with their normal diet for the period of three months. Their base line lipid profile and body weight was recorded at start of treatment and were advised to come for check-up, fortnightly.
International Journal of Medical Science in Clinical Research and Review Vol 03, Issue 02,April – 2020 Page |
229
When duration of study was over, their lipid profile and body weight was measured and compared statistically with pre-treatment values. Three months treatment with 5 grams of ginger decreased total cholesterol from 233.11±1.53 mg/dl to 198.44±1.23 mg/dl, LDL cholesterol reduced from 202.21±1.88 mg/dl to 187.72± 1.98 mg/dl, reduced body weight from 76.01±2.66 kg to 72.80±1.87 kg. Both plasma total cholesterol and LDL cholesterol reduction was statistically significant, but body weight decrease was non-significant when analyzed biostatistically.
A 63-year-old Caucasian woman presented with depressive syndrome and elevated liver enzymes but no extrahepatic manifestations. Liver biopsy showed cirrhosis with moderate activity and pericentral necrosis. She was treated with prednisone and azathioprine, achieving remission within 3 months. Azathioprine was stopped after 2 years due to normal liver enzymes and decreased IgG levels. Her case illustrates treatment and monitoring of autoimmune hepatitis.
Albumin versus fresh frozen plasma in managing diuretic resistant edema in ch...iosrphr_editor
This study was carried out to compare the efficacy, cost effectiveness and outcome of albumin with fresh frozen plasma (FFP) in the treatment of diuretic resistant edema in childhood idiopathic nephrotic syndrome.Methods: Fifty four patients with idiopathic NS were enrolled in this prospective analytic study. Patients with moderate to severe edema with serum albumin <15 gm/L were given albumin and FFP dividing into two groups. Group-A, received intravenous albumin- 1 gm/kg/day and Group-B intravenous FFP 15ml/kg/day. Total number of albumin and FFP infusion were determined by edema reduction. Cost effectiveness was also calculated. Results: Diagnosis of NS and biochemical parameters were same in both groups. Dry weight was achieved in Group-A in 6.66± 3.710 days and in Group-B 6.66± 3.038 days. In Group-A the number of albumin infusion required was 1.44±0.697 and Group-B FFP infusion required was 3.11± 1.5 (p=0.0001). Group A needed 4608.00 ($57.6) taka for albumin whereas Group B needed only 2177.00($ 27.2) taka for FFP (p=0.0001). No significant complications were observed in both the groups.Conclusion: FFP costs half than albumin and same duration required reducing edema but the cost-effectiveness may place FFP as a better choice especially in developing countries of the world.
This document summarizes guidelines for managing lupus nephritis from KDIGO 2023. It recommends treating active proliferative lupus nephritis classes III/IV with glucocorticoids plus mycophenolic acid, low-dose intravenous cyclophosphamide, or belimumab added to one of those. It provides guidance on induction therapy duration, preferred maintenance agents, and managing treatment failure or unsatisfactory response. Trial results are presented for therapies involving belimumab, calcineurin inhibitors, voclosporin, and different immunosuppressive regimens.
This document summarizes current treatment guidelines for lupus nephritis. It defines lupus nephritis based on ACR criteria and recommends an early renal biopsy. For initial treatment of proliferative lupus nephritis (classes III/IV), guidelines differ on whether cyclophosphamide or mycophenolate mofetil is preferred. Maintenance therapy with mycophenolate mofetil or azathioprine with low-dose steroids is recommended, with mycophenolate mofetil showing better outcomes. Immunosuppression should be continued for at least one year after complete remission is achieved.
Background: High serum phosphate level is associated with increased CVD morbidity and mortality in CKD patients. We sought to compare the efϐicacy of non-calcium containing phosphate binder Sevelamer Carbonate (SC) with Lanthanum Carbonate (LC) in patients with CKD stage 3-5.
1) The document describes a 52-week placebo-controlled trial that compared evolocumab (a monoclonal antibody that inhibits PCSK9) to placebo in patients with hyperlipidemia receiving background lipid-lowering therapy.
2) The primary endpoint was the percent change from baseline in LDL-C levels at week 52. Evolocumab produced a 57% reduction in LDL-C on average compared to placebo.
3) Evolocumab also significantly reduced levels of other atherogenic lipids like apolipoprotein B and lipoprotein(a) while modestly increasing HDL cholesterol. More than 80% of patients receiving evolocumab achieved a target LDL-C level of under 70 mg/dL.
Similar to lesinurad in combination with allopurinol a randomised, double blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational clear 2 study) (20)
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Currency notes and conventional banking may disappear within the next 10 years as digital transactions become more widely used. Set top boxes and wired chargers could also become obsolete as streaming devices and wireless charging see greater adoption. Vehicles that run on fossil fuels are projected to vanish as renewable energy sources and electric vehicles provide more sustainable transportation options in the future. Physical identity cards may no longer be needed if a single digital identity is established for universal use.
This document outlines guidelines for tuberculosis treatment under India's Revised National Tuberculosis Control Programme (RNTCP) using a daily drug regimen rather than the previous thrice-weekly regimen. It describes the treatment protocols for new and previously treated TB cases, including drug combinations, dosages, treatment duration and monitoring. A key change is the use of fixed-dose combination drugs packaged for daily administration over 4 weeks. Strict treatment supervision and support is emphasized to ensure patient adherence and cure.
The thin-fat phenotype seen in South Asians, especially Indians, may be due to small positive energy balances from lifestyle changes like reduced physical activity and consumption of high-fat, high-sugar foods. This can lead to excess fat accumulation even at a low BMI. Rural to urban migration increases risk as lifestyles transition. The thin-fat phenotype may represent a transitional phase as previously thin individuals gain weight on low muscle frames, rather than a unique genotype. Understanding its causes and interactions with an urbanizing environment is important for addressing metabolic disease risk in these populations.
This document provides guidelines for the management of snakebites in South-East Asia. It covers the epidemiology of snakebites in the region, describing the diverse venomous snake species and the variation in species between countries. Snakebite is a major public health issue, resulting in many deaths and disabilities annually. The document provides guidance on the clinical assessment and treatment of snakebite patients, including first aid, antivenom administration, and supportive care. It aims to equip medical professionals with the knowledge to effectively treat snakebites.
The document discusses the importance of maintaining good hygiene habits like handwashing to prevent the spread of diseases. It notes that germs can spread through direct contact with infected individuals or indirectly through surfaces they've touched. Proper handwashing with soap and water is the most effective way to kill germs and stop their transmission to keep yourself and others healthy.
Psoriatic arthritis is a common inflammatory disease that affects the joints and skin. It develops in up to 30% of patients with psoriasis. The document discusses the clinical features, epidemiology, and burden of psoriatic arthritis. It describes the different subtypes including oligoarticular, polyarticular, distal, arthritis mutilans, and axial subtypes. It also discusses diagnostic criteria, prevalence, disease manifestations including enthesitis and dactylitis, and the psychological and functional burdens on patients. Improved understanding of disease mechanisms has led to more effective targeted therapies.
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Hepatic encephalopathy (HE) refers to brain dysfunction caused by liver disease and can range from subclinical to coma. Minimal HE (MHE) and grade I HE are now classified as covert HE (CHE) due to difficulty distinguishing without tests. CHE affects 40-84% of cirrhotics and is associated with reduced quality of life, impaired skills, and survival. Treatment of CHE is justified given these consequences. Lactulose, rifaximin, probiotics, and diet modifications can improve CHE symptoms. Specialized tests are needed to diagnose MHE, while CHE screening tools like SIP-CHE can provide rapid assessment.
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This document summarizes research on the human intestinal microbiome. It discusses how culture-independent techniques have revealed the enormous diversity of microbes in the human gut. The gut microbiota plays important roles in immunity, metabolism, and other bodily functions, and imbalances are associated with various diseases. The composition of the gut microbiota changes over a person's lifetime from birth through adulthood and old age due to factors like mode of birth, diet, antibiotic use, and age-related immune changes. Understanding these dynamics may lead to new disease treatments targeting the gut microbiome.
This study analyzed bleeding events among 5,170 patients from the CHANCE trial who received dual antiplatelet therapy (clopidogrel plus aspirin) or aspirin alone for minor stroke or transient ischemic attack. A total of 101 bleeding events occurred, with no significant difference in rates between the treatment groups. However, patients with minor strokes had a higher risk of bleeding than those with transient ischemic attacks. Being elderly, male, and having a history of aspirin or proton pump inhibitor use were associated with greater bleeding risk, while higher body mass index was protective against bleeding.
This document provides an introduction to a review article about the clinical approach to diagnosing movement disorders. It discusses the prevalence of common movement disorders like Parkinson's disease and essential tremor. The key to diagnosis is accurately classifying the type of movement disorder present based on the clinical presentation. This involves defining the dominant abnormal movement as well as any associated neurological or non-neurological features. Once classified, the movement disorder can guide further diagnostic testing and help establish a differential diagnosis. The review will cover approaches to diagnosing akinetic-rigid syndromes and hyperkinetic disorders like tics, chorea, dystonia and tremor.
This document provides diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), including:
1) Clinical criteria for typical and atypical CIDP with inclusion/exclusion factors.
2) Definite, probable, and possible electrophysiological criteria involving compound muscle action potential tests.
3) Supportive diagnostic criteria including cerebrospinal fluid analysis, MRI findings, nerve conduction studies, and nerve biopsy results.
It also outlines inclusion/exclusion criteria and supportive criteria specifically for diagnosing pure sensory CIDP without motor involvement.
- A young lady presented with headache, fever and gradual loss of vision with other neurological symptoms and was diagnosed with tuberculous meningitis based on investigations. She developed drug-induced liver injury during treatment and her anti-tubercular treatment was modified. She also developed seizures and hydrocephalus requiring VP shunt placement. Her condition is being closely monitored during anti-tubercular treatment and management of complications.
Terrorism & clinical medicine.namal 1arnab ghosh
The document discusses various biological agents that could potentially be used for terrorism purposes. It covers microbial bioterrorism, categories of biological weapons including category A, B and C agents. It then provides more detailed information about specific biological agents like anthrax, plague, smallpox, botulism toxin, tularemia and viral hemorrhagic fevers including their transmission, clinical features, diagnosis and treatment.
Snake bites are a major public health issue in India, with the highest mortality rate in the world according to WHO estimates of 83,000 bites and 11,000 deaths annually. There are 216 species of snakes found in India, of which 52 are poisonous. The main poisonous snake families are the elapidae which includes cobras, kraits, and sea snakes; viperidae which includes Russell's vipers, saw-scaled vipers and sand vipers. Snake venom is mostly proteins including enzymes, toxins, and neurotoxins. Clinical effects of snake bites vary and can be categorized into 5 syndromes based on symptoms - local envenoming, bleeding/clotting disturbances, paralysis, renal failure
The document provides guidelines for the diagnosis and management of sepsis from 2012 and 2016. It outlines key differences between the 2012 and 2016 guidelines. The 2012 guidelines focused on early goal-directed therapy and resuscitation, while the 2016 guidelines emphasize monitoring for sepsis at the hospital level, obtaining cultures before antibiotics, shorter antibiotic durations, conservative fluid strategies, and incorporating palliative care principles earlier through discussions of goals of care. Investigational therapies aimed at modulating the immune response are also discussed.
A 35-year-old female presented with subacute onset right hemiparesis, fever, headache, and seizures over the past three days. Imaging revealed a cerebral venous thrombosis involving the superior sagittal and right sigmoid sinuses. She was treated with anticoagulation and antiepileptic medications.
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A 47-year-old male presented with abdominal pain and vomiting for one day. He has a history of significant alcohol consumption. On examination, his abdomen was tender in the epigastric region. Laboratory tests revealed elevated amylase and lipase levels consistent with acute pancreatitis, likely due to alcohol use. A CT scan showed signs of acute necrotizing pancreatitis including pancreatic necrosis, peripancreatic fat stranding, and mild ascites. The patient's history and clinical signs were consistent with acute pancreatitis likely caused by alcohol abuse.
This document provides an overview of osteoporosis including its definition, epidemiology, pathophysiology, causes, clinical features, diagnosis, and treatment. Some key points include:
- Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is defined by the WHO as a bone density 2.5 standard deviations below the mean.
- It is a major global health problem, particularly affecting post-menopausal women and the elderly. Lifetime risk of osteoporotic fractures is 30-50% in females and 15-30% in males.
- Causes include failure to achieve peak bone mass, increased bone resorption, and inadequate bone formation
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The skin is the largest organ and its health plays a vital role among the other sense organs. The skin concerns like acne breakout, psoriasis, or anything similar along the lines, finding a qualified and experienced dermatologist becomes paramount.
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lesinurad in combination with allopurinol a randomised, double blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational clear 2 study)
1. EXTENDED REPORT
Lesinurad in combination with allopurinol:
a randomised, double-blind, placebo-controlled study
in patients with gout with inadequate response to
standard of care (the multinational CLEAR 2 study)
Thomas Bardin,1
Robert T Keenan,2
Puja P Khanna,3
Jeff Kopicko,4
Maple Fung,5
Nihar Bhakta,5
Scott Adler,6
Chris Storgard,5
Scott Baumgartner,7
Alexander So8
Handling editor Tore K Kvien
▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
annrheumdis-2016-209213).
For numbered affiliations see
end of article.
Correspondence to
Professor Thomas Bardin,
Rhumatologie, Hôpital
Lariboisière, Assistance
Publique Hôpitaux de Paris,
2, rue A Paré, 75010 Paris;
thomas.bardin@aphp.fr
JK and CS are former
employees.
Received 17 January 2016
Revised 25 August 2016
Accepted 5 October 2016
To cite: Bardin T,
Keenan RT, Khanna PP,
et al. Ann Rheum Dis
Published Online First:
[please include Day Month
Year] doi:10.1136/
annrheumdis-2016-209213
ABSTRACT
Objectives Determine the efficacy and safety of daily
lesinurad (200 or 400 mg orally) added to allopurinol in
patients with serum uric acid (sUA) above target in a
12-month, randomised, phase III trial.
Methods Patients on allopurinol ≥300 mg (≥200 mg
in moderate renal impairment) had sUA level of
≥6.5 mg/dL (≥387 mmol/L) at screening and two or
more gout flares in the prior year. Primary end point was
the proportion of patients achieving sUA level of
<6.0 mg/dL (<357 mmol/L) (month 6). Key secondary
end points were mean gout flare rate requiring treatment
(months 7 through 12) and proportions of patients with
complete resolution of one or more target tophi (month
12). Safety assessments included adverse events and
laboratory data.
Results Patients (n=610) were predominantly male,
with mean (±SD) age 51.2±10.90 years, gout duration
11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL
(410±71 mmol/L). Lesinurad at 200 and 400 mg doses,
added to allopurinol, significantly increased proportions
of patients achieving sUA target versus allopurinol-alone
therapy by month 6 (55.4%, 66.5% and 23.3%,
respectively, p<0.0001 both lesinurad+allopurinol
groups). In key secondary end points, there were no
statistically significant treatment-group differences
favouring lesinurad. Lesinurad was generally well
tolerated; the 200 mg dose had a safety profile
comparable with allopurinol-alone therapy. Renal-related
adverse events occurred in 5.9% of lesinurad 200 mg
+allopurinol, 15.0% of lesinurad 400 mg+allopurinol
and 4.9% of allopurinol-alone groups, with serum
creatinine elevation of ≥1.5× baseline in 5.9%, 15.0%
and 3.4%, respectively. Serious treatment-emergent
adverse events occurred in 4.4% of lesinurad 200 mg
+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol
and in 3.9% of allopurinol-alone groups, respectively.
Conclusion Lesinurad added to allopurinol
demonstrated superior sUA lowering versus allopurinol-
alone therapy and lesinurad 200 mg was generally well
tolerated in patients with gout warranting additional
therapy.
Trial registration number NCT01493531.
INTRODUCTION
Gout is an inflammatory arthritis characterised by
the deposition of monosodium urate (MSU) crystals
in the joints, tendons and other connective tissues.
Crystal deposition secondary to long-standing
hyperuricemia can be reversed by lowering the con-
centration of serum uric acid (sUA) below the MSU
saturation point—leading, in the long term, to the
potential disappearance of signs and symptoms of
gout. As a result, current management guidelines
recommend maintenance of sUA to <6.0 mg/dL
(<357 mmol/L) in patients with gout.1–3
Allopurinol is recommended as a first-line urate-
lowering therapy (ULT).2 4
However, clinical trials
have demonstrated that >50% of patients do not
achieve sustained reductions in sUA at the most
commonly used allopurinol dose of 300 mg.5–8
Lesinurad (RDEA594) is a novel, selective uric acid
reabsorption inhibitor (SURI) for treatment of gout
in combination with xanthine oxidase inhibitors.
Lesinurad inhibits URAT1, a uric acid transporter
responsible for the reabsorption of uric acid from
the renal tubular lumen.9–11
Lesinurad in combin-
ation with allopurinol therefore provides a dual
mechanism for sUA lowering—an increase in excre-
tion of uric acid and a reduction in urate production.
Clinical studies have demonstrated that lesinurad
in combination with allopurinol reduces mean
sUA concentrations and increases proportions of
patients who achieve sUA targets.12–14
The current
phase III study—Combining Lesinurad with
Allopurinol Standard of Care in Inadequate
Responders (CLEAR 2)—is one of two replicate,
randomised, double-blind, placebo-controlled, mul-
ticentre studies to investigate lesinurad in combin-
ation with allopurinol in patients with gout.
CLEAR 1 was performed within the USA, included
603 patients with gout and provided outcomes
similar to the CLEAR 2 study.15
METHODS
Study design
CLEAR 2 was an international, phase III trial to
investigate the efficacy and safety of two lesinurad
doses (200 or 400 mg oral, once daily) in combin-
ation with allopurinol, versus allopurinol combined
with placebo (the control arm), in patients
demonstrating inadequate response to standard-
of-care allopurinol (ClinicalTrials.gov Identifier:
NCT01493531). The study was conducted in 12
countries in Europe, North America, South Africa,
Australia and New Zealand between December
2011 and July 2014.
Bardin T, et al. Ann Rheum Dis 2016;0:1–10. doi:10.1136/annrheumdis-2016-209213 1
Clinical and epidemiological research
ARD Online First, published on November 7, 2016 as 10.1136/annrheumdis-2016-209213
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
group.bmj.comon November 16, 2016 - Published byhttp://ard.bmj.com/Downloaded from
2. CLEAR 2 included a screening period of approximately
28 days, including a run-in of approximately 14 days on gout flare
prophylaxis and 12-month double-blind treatment (figure 1). The
study was conducted in accordance with Independent Ethics
Committee E6 Good Clinical Practice, the Declaration of
Helsinki (October 2008) and all applicable local regulatory
requirements.
Patients
Male or female patients aged 18–85 years with a diagnosis of
gout, body mass index <45 kg/m2
, inadequate hypouricaemic
response to standard-of-care allopurinol and two or more gout
flares in the previous 12 months were eligible for study inclu-
sion. Patients were included if they met the 1977 American
Rheumatism Association preliminary classification criteria for
gout.16
Patients were required to have received allopurinol as
the sole ULT for ≥8 weeks prior to screening at a dose assessed
medically appropriate by the treating physician (minimum
300 mg/day (200 mg in moderate renal impairment)17
up to
800 or 900 mg, depending on locally approved dose). sUA was
required to be ≥6.5 mg/dL (≥387 mmol/L) at screening and
≥6.0 mg/dL (≥357 mmol/L) approximately 7 days prior to start
of treatment on day 1.
Patients with estimated creatinine clearance (eCrCl) <30 mL/
min were excluded from study. Patients with a history of kidney
stones were permitted. Complete exclusion criteria are included
in the online supplementary material 1.
Study medications
Eligible patients were randomised by double-blind method to
one of three treatment groups (lesinurad 200 mg, lesinurad
400 mg or placebo) in 1:1:1 ratio, added to continued treatment
with allopurinol at pre-study dose. Randomisation at study sites
used a centralised Interactive Voice Response System/Interactive
Web Response System.
Doses of lesinurad or matching placebo were taken once daily
in the morning with food and one cup of water. Compliance
was assessed from dispensing records and verification of
returned medication packaging. Concomitant medication use
was recorded at each study visit.
Gout flare prophylaxis was initiated at day −14, that is, the
same time as sponsor-provided allopurinol. Prophylaxis con-
sisted of colchicine (0.5 or 0.6 mg/day, as locally available) or a
non-steroidal anti-inflammatory drug (NSAID, dosed according
to local prescribing practice, with or without proton-pump
inhibitor) for patients who were intolerant to or had contraindi-
cations to colchicine. Gout flare prophylaxis was continued
through month 5, unless patients became intolerant or devel-
oped toxicity to prophylaxis.
Patients were encouraged to drink 2 L of fluid a day and
remain well hydrated, following American College of
Rheumatology guidelines for management of gout.2
Assessments
Efficacy assessments
The primary efficacy end point was the proportion of patients
in each treatment group with sUA <6.0 mg/dL (<357 mmol/L)
by month 6. Other sUA-related end points included proportions
of patients with sUA <6.0 mg/dL (<357 mmol/L), <5.0 mg/dL
(<297 mmol/L) and <4.0 mg/dL (<238 mmol/L) and mean
absolute and mean percentage changes from baseline in sUA at
each visit.
Two key secondary end points included: (1) mean rate of
gout flares requiring treatment for the 6-month period from
end of month 6 to end of month 12, reported on a daily elec-
tronic patient diary. This key secondary end point included only
Figure 1 CLEAR 2 trial design is shown. *200 mg permitted for renally impaired. Maximum allopurinol dose: 800 or 900 mg, according to local
label. Randomisation was stratified at day −7 by renal function (ie, estimated eCrCl ≥60 vs <60 mL/min, calculated by the Cockcroft-Gault formula
using ideal body weight) and by tophus status during screening (ie, one or more tophus versus no tophi). eCrCl, estimated creatinine clearance; sUA,
serum uric acid.
2 Bardin T, et al. Ann Rheum Dis 2016;0:1–10. doi:10.1136/annrheumdis-2016-209213
Clinical and epidemiological research
group.bmj.comon November 16, 2016 - Published byhttp://ard.bmj.com/Downloaded from
3. clinically relevant gout flares, which were those requiring either
an increase in current medication or new medication and (2)
proportion of patients with target tophi at baseline who experi-
enced complete resolution of one or more target tophi by
month 12, that is, 100% decrease in tophus area. Target tophi
(up to five per patient) were tophi on the hands/wrists and/or
feet/ankles measured by digital Vernier callipers at ≥5 and
≤20 mm in longest diameter.18
Permitted treatments for gout
flares were colchicine, analgesics and/or anti-inflammatory medi-
cations, including oral and intra-articular corticosteroids.
Safety assessments
Safety assessments included treatment-emergent adverse events
(TEAEs; coded by Medical Dictionary for Regulatory Activities
(V.14.0)), clinical laboratory data, physical examination, ECG
and vital signs. Adverse events (AEs) of special interest included
renal and cardiovascular (CV) safety assessments.
Assessments of renal safety included renal-related and kidney
stone TEAEs (see online supplementary material 2) and clinical
laboratory data, including serum creatinine (sCr), creatine
kinase, urine protein-to-creatinine ratio and eCrCl levels. CV
safety was of special interest because of the known high rates of
CV risk factors in patients with gout.19 20
An independent
Cardiovascular Events Adjudication Committee (CEAC) rou-
tinely assessed AEs for potential CV relationship, with categor-
isation into major adverse CV events (MACEs) and non-MACE
end points (see online supplementary material 3).21
Statistical analyses
Comparisons of response proportions based on sUA level
between each lesinurad plus allopurinol group and the
allopurinol-alone group were performed using the
Cochran-Mantel-Haenszel (CMH) test statistic, stratified by day
−7 renal function and tophus status during screening. A
Bonferroni correction was used for the primary end point for
each of the two treatment comparisons with allopurinol-alone
therapy at an α level of 0.025. Testing of the key secondary end
points hierarchically at an α level of 0.05 was gated on both
dose contrasts being statistically significant for the primary end
point. If only one of the primary end point dose contrasts was
significant, then α=0.025 for each key secondary end point
within the surviving dose. All other efficacy end points were
evaluated at α=0.05 (nominal p value), two-sided, without
multiplicity adjustment. Results for the primary end point of
sUA response are expressed as proportions and p values.
Patients with missing values at month 6 or month 12 for any
reason were considered non-responders (non-responder imput-
ation, NRI).22
Key secondary end points were analysed using
negative binomial regression (gout flares) or CMH test (tophus
response). Mean rates of gout flares were adjusted for day −7
renal function, tophus status at screening and length of exposure
to randomised study medication. The time points and analytical
methods used in the study were agreed with multiple regulatory
agencies.
Safety data are listed by treatment arm and are not subjected
to statistical testing. TEAEs are coded by system organ class and
preferred term and are listed according to incidence, severity,
relation to study medication and relation to discontinuation. To
better identify potential clinically relevant changes in sCr
related to lesinurad by minimising discrepancies due to intra-
subject variability, baseline sCr was defined as the highest value
within 14 days prior to first dose of study medication. Relative
increase in sCr (ie, ≥1.5× and ≥2.0× the baseline level at any
time) was selected as the most clinically relevant sCr
assessment.23 24
Resolution of sCr elevation was defined as an
sCr value returned to ≤1.2× baseline.
A sample size of approximately 600 patients was planned to
be recruited, for an allocation of approximately 200 patients to
each treatment arm. This sample size was calculated to provide
greater than 90% power to detect a difference in response rate
between treatment groups if the allopurinol-alone group had a
30% response rate and the lesinurad groups had response rates
as low as 48% using Fisher’s exact test, adjusting for multiplicity
with α=0.025, two-sided, for each test.
All randomised patients who received at least one dose of
study medication were included in the intent-to-treat (ITT)
population, which was the primary population for efficacy and
safety assessments.
RESULTS
Patient disposition
Of the 2199 patients screened, 611 were randomised at 152
sites. Of the 611 randomised patients, 610 received at least one
dose of study medication (figure 2).
Demographic characteristics and clinical history
Demographics and baseline disease characteristics were similar
between treatment groups (table 1). Patients generally had long-
standing symptomatic gout (mean (±SD) time since diagnosis
11.5±9.3 years) and elevated baseline sUA (mean 6.9±1.2 mg/dL
(410±71 mmol/L)), with high rates of one or more predefined
comorbidities (ie, CV risk factors or kidney stones) at 79.2%.
Most patients (84.1%) received allopurinol at a daily dose of
300 mg, with 6.6% receiving <300 mg and 9.3% receiving
>300 mg; the overall dose range was 200–900 mg.
Study medications
Proportions of patients exhibiting ≥80% compliance with study
medication were 97.6%, 94.1% and 94.5% in the
allopurinol-alone, lesinurad 200 mg+allopurinol and lesinurad
400 mg+allopurinol groups, respectively.
Efficacy assessments
Primary end point of sUA response and secondary sUA end points
Proportions of patients achieving sUA level of <6.0 mg/dL
(<357 mmol/L) by month 6 (the primary end point) were
23.3%, 55.4% and 66.5% in the allopurinol-alone, lesinurad
200 mg+allopurinol and lesinurad 400 mg+allopurinol groups,
respectively, using NRI—significant differences were identified
for both lesinurad+allopurinol groups versus allopurinol-alone
(p<0.0001; CMH test) (figure 3).
Subgroup analyses based on age, sex, race, baseline sUA,
comorbidities, renal function and thiazide diuretic use provided
results consistent with primary analysis of the ITT population
(see online supplementary material 4 for renal function and
diuretic analyses).
Proportions of patients achieving the sUA target of
<6.0 mg/dL (<357 mmol/L) were greater in the lesinurad
200 mg+allopurinol and lesinurad 400 mg+allopurinol versus
allopurinol-alone group at all monthly assessments from month 1
to month 12 (nominal p<0.0001, all comparisons). Proportions
of patients achieving sUA level of <5.0 mg/dL (<297 mmol/L)
and <4.0 mg/dL (<238 mmol/L) were also greater in both
lesinurad+allopurinol groups versus allopurinol-alone group at
each monthly visit (sUA <5.0 mg/dL (<297 mmol/L): nominal
p<0.0001, both comparisons; sUA <4.0 mg/dL (<238 mmol/L):
nominal p<0.0001, both comparisons, except p<0.01 at
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4. month 1, lesinurad 200 mg+allopurinol). Figure 3 shows propor-
tions of patients at each sUA threshold by months 6 and 12.
Mean sUA levels were lower in both lesinurad+allopurinol
groups versus allopurinol-alone group at all time points (nominal
p<0.001, both comparisons compared with allopurinol-alone
therapy) (figure 4).
Secondary end point: gout flares requiring treatment
The gout flare rate and the proportions of patients with gout
flares requiring treatment were low and similar in all groups
throughout the study. Mean (±SE) rates of gout flares requiring
treatment from the end of month 6 to end of month 12 were
0.83±0.13 for allopurinol-alone group versus 0.73±0.12 and
0.77±0.13, respectively, in the lesinurad 200 mg+allopurinol
and lesinurad 400 mg+allopurinol groups (p=0.57 and 0.75 vs
allopurinol-alone group). Proportions of patients with a gout
flare requiring treatment through the study are shown in online
supplementary figure S2.
Secondary end point: tophus resolution
The numbers of patients with one or more target tophi at base-
line were low: 33, 35 and 29 in the allopurinol-alone, lesinurad
200 mg+allopurinol and lesinurad 400 mg+allopurinol groups,
respectively. In these respective groups, 33.3%, 31.4% and
27.6% of patients achieved complete resolution of one or more
target tophi by month 12 (p>0.05, both lesinurad+allopurinol
groups vs allopurinol-alone group).
Safety assessments
Adverse events
TEAEs were reported in 70.9%, 74.5% and 80.5% of the
allopurinol-alone, lesinurad 200 mg+allopurinol and lesinurad
400 mg+allopurinol groups, respectively (table 2). The majority
of TEAEs in each group had a maximum severity of grade 1 or
grade 2, based on Rheumatology Common Toxicity Criteria.25
The most common individual TEAEs—reported for
allopurinol-alone, lesinurad 200 mg+allopurinol and lesinurad
400 mg+allopurinol groups, respectively—were upper respira-
tory tract infection (10.2%, 6.9%, 15.0%), hypertension (4.9%,
8.3%, 8.0%), arthralgia (4.4%, 11.8%, 3.0%), increased blood
creatinine (3.4%, 3.9%, 9.5%) and diarrhoea (3.4%, 4.9%,
7.0%). The most common grade 3 or grade 4 TEAEs in these
respective groups were increased blood creatine kinase (1.5%,
0.5%, 1.5%) and myocardial infarction (MI) (0%, 0%, 1.5%).
Serious TEAEs were reported in 3.9%, 4.4% and 9.5%
of patients, respectively (table 2). Two deaths occurred in the
lesinurad 400 mg+allopurinol group (pulmonary oedema and
gastric cancer, respectively). TEAEs led to study-medication dis-
continuation in 5.3%, 3.4% and 9.5% of the allopurinol-alone,
lesinurad 200 mg+allopurinol and lesinurad 400 mg+allopur-
inol groups, respectively; the most common TEAE leading to
discontinuation was increased blood creatinine (1.0%, 0% and
2.5%, respectively).
Renal safety analyses
Renal-related TEAEs occurred in 4.9%, 5.9% and 15.0%, of
allopurinol-alone, lesinurad 200 mg+allopurinol and lesinurad
Figure 2 Patient disposition is shown. a
Screened was defined as signing an informed consent form; b
2 deaths reported for non-randomised
patients during screening and c
completed the study with or without completing randomised study medication. One additional death occurred in the
LESU 400 mg+ALLO group. The subject experienced a serious adverse event and withdrew from the study. The primary reason for study withdrawal
was reported as ‘adverse event’. Of the 1538 screen failures, 1183 were related to inclusion criteria, 252 to exclusion criteria, 94 to both inclusion
and exclusion criteria and 9 to other. ALLO, allopurinol; LESU, lesinurad.
4 Bardin T, et al. Ann Rheum Dis 2016;0:1–10. doi:10.1136/annrheumdis-2016-209213
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5. Table 1 Demographic and baseline disease characteristics (intent-to-treat population)
ALLO alone (n=206) Lesinurad 200 mg+ALLO (n=204) Lesinurad 400 mg+ALLO (n=200) Total (n=610)
Sex (n (%))
Male 196 (95.1) 197 (96.6) 194 (97.0) 587 (96.2)
Female 10 (4.9) 7 (3.4) 6 (3.0) 23 (3.8)
Race (n (%))
White 155 (75.2) 167 (81.9) 160 (80.0) 482 (79.0)
Black or African-American 22 (10.7) 15 (7.4) 21 (10.5) 58 (9.5)
Asian 14 (6.8) 10 (4.9) 9 (4.5) 33 (5.4)
Native Hawaiian or other Pacific Islander 5 (2.4) 3 (1.5) 2 (1.0) 10 (1.6)
American-Indian or Alaska Native 1 (0.5) 1 (0.5) 0 2 (0.3)
Other 8 (3.9) 4 (2.0) 6 (3.0) 18 (3.0)
Missing 0 0 1 (0.5) 1 (0.2)
Age (years)
Mean (SD) 51.4 (10.56) 51.0 (11.11) 51.3 (11.08) 51.2 (10.90)
Min, max 21, 80 21, 82 18, 80 18, 82
BMI (kg/m2
)
Mean (SD) 33.87 (6.19) 34.67 (6.43) 33.81 (6.68) 34.12 (6.44)
Min, max 21.91, 56.27 22.55, 55.63 22.76, 69.36 21.91, 69.36
Duration since gout diagnosis (years)
Mean (SD) 11.31 (9.38) 12.25 (9.75) 11.02 (8.59) 11.53 (9.26)
Min, max 0.2, 53.0 0.5, 45.0 0.0, 47.4 0.0, 53.0
Presence of tophi at screening (n (%))
Yes 48 (23.3) 49 (24.0) 47 (23.5) 144 (23.6)
No 158 (76.7) 155 (76.0) 153 (76.5) 466 (76.4)
Presence of ≥1 target tophus at baseline (n (%))
Yes 33 (16.0) 35 (17.2) 29 (14.5) 97 (15.9)
No 173 (84.0) 169 (82.8) 171 (85.5) 513 (84.1)
No. of target tophi at baseline
n 33 35 29 97
Mean (SD) 2.2 (1.36) 2.0 (1.34) 2.5 (1.53) 2.2 (1.40)
Min, max 1, 5 1, 5 1, 5 1, 5
No. of gout flares in the past 12 months
Mean (SD) 5.8 (4.92) 6.7 (7.01) 6.1 (5.65) 6.2 (5.93)
Min, max 2, 30 2, 50 2, 48 2, 50
Renal function at baseline (mL/min) (n (%))
eCrCl ≥90 72 (35.0) 80 (39.2) 85 (42.5) 237 (38.9)
eCrCl <90 133 (64.6) 124 (60.8) 114 (57.0) 371 (60.8)
eCrCl ≥60 165 (80.1) 175 (85.8) 170 (85.0) 510 (83.6)
eCrCl <60 40 (19.4) 29 (14.2) 29 (14.5) 98 (16.1)
CV risk factors (n (%))
Hypertension 141 (68.4) 131 (64.2) 121 (60.5) 393 (64.4)
Hyperlipidaemia 76 (36.9) 86 (42.2) 93 (46.5) 255 (41.8)
Type 2 diabetes 28 (13.6) 31 (15.2) 26 (13.0) 85 (13.9)
History of kidney stones (n (%)) 28 (13.6) 23 (11.3) 18 (9.0) 69 (11.3)
Baseline thiazide/thiazide-like
diuretic use (n (%))
37 (18.0) 43 (21.1) 35 (17.5) 115 (18.9)
sUA at baseline (mg/dL) (mmol/L)
Mean (SD) 7.0 (1.3) (416 (75)) 6.8 (1.1) (407 (66)) 6.9 (1.2) (410 (71)) 6.9 (1.2) (410 (71))
Min, max 3.4, 11.3 (202, 672) 4.0, 11.3 (238, 672) 3.8, 11.0 (226, 654) 3.4, 11.3 (202, 672)
sUA category at baseline (n (%))
<8.0 mg/dL (<476 mmol/L) 162 (78.6) 177 (86.8) 164 (82.0) 503 (82.5)
≥8.0 mg/dL (≥476 mmol/L) 44 (21.4) 27 (13.2) 36 (18.0) 107 (17.5)
Continued
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6. 400 mg+allopurinol groups, respectively. The most common
renal-related TEAEs in these respective groups were increased
blood creatinine (3.4%, 3.9%, 9.5%), increased blood urea
(0%, 2.0%, 1.5%) and renal failure (0.5%, 1.0%, 1.5%). One
patient (0.5%) in the allopurinol-alone group experienced a
serious renal-related TEAE, versus no patients in the lesinurad
200 mg+allopurinol and two patients (1.0%) in the lesinurad
400 mg+allopurinol group. Kidney stone TEAEs were reported
in 0.5%, 0% and 3.0%, respectively.
sCr elevation ≥1.5× baseline occurred in 3.4% (n=7), 5.9%
(n=12) and 15.0% (n=30) of allopurinol-alone, lesinurad
200 mg+allopurinol and lesinurad 400 mg+allopurinol groups,
respectively. sCr elevation ≥1.5× was transient and reversible in
most cases and the majority of sCr elevations resolved by the
time of the next assessment; there were three unresolved sCr
elevations in the allopurinol-alone group at last visit versus none
in the lesinurad 200 mg+allopurinol and seven in the lesinurad
400 mg+allopurinol group (see online supplementary table S1).
sCr elevation ≥2.0× baseline occurred in 0%, 2.0% (n=4) and
8.0% (n=16) of patients, respectively. Again, most elevations
≥2.0× baseline were transient and reversible; no sCr elevations
≥2.0× were unresolved at last visit in the lesinurad 200 mg
+allopurinol group and five cases were unresolved in the lesi-
nurad 400 mg+allopurinol group. In approximately two-thirds
of sCr elevations, resolution occurred while patients continued
on study medication.
In all treatment groups, proportions of patients with an sCr
elevation ≥1.5× baseline tended to be higher for patients (1)
who were taking an NSAID than colchicine; (2) who did not
achieve target sUA at month 6 versus responders and (3) who
had one or more tophi at screening versus those without tophi,
although small subgroup sizes render interpretation difficult (see
online supplementary table S2). There was no apparent associ-
ation between sCr elevation and baseline renal function or other
concomitant medications.
Renal function remained stable across the treatment groups,
as measured by mean (SD) changes in eCrCl, from baseline to
last value. Mean (±SD) changes in eCrCl in the
allopurinol-alone, lesinurad 200 mg+allopurinol and lesinurad
400 mg+allopurinol groups were 3.0±9.7, −0.5±11.5 and
−5.7±13.9 mg/dL, respectively, from baseline to last value on
treatment and were 1.8±11.7, 2.7±10.0 and 1.1±24.2 mg/dL
from baseline to last value off treatment at follow-up (in patients
not entering a separate extension study, n=133).
CV safety analyses
TEAEs were adjudicated as CV events in 5.3% (n=11 patients),
3.9% (n=8 patients) and 3.0% (n=6 patients) of
allopurinol-alone, lesinurad 200 mg+allopurinol and lesinurad
400 mg+allopurinol groups, respectively. CEAC-adjudicated cri-
teria for MACE were met by three patients (four events, includ-
ing three MIs and one death due to pulmonary oedema), all in
Table 1 Continued
ALLO alone (n=206) Lesinurad 200 mg+ALLO (n=204) Lesinurad 400 mg+ALLO (n=200) Total (n=610)
Type of gout flare prophylaxis at baseline (n (%))
Colchicine 159 (77.2) 181 (88.7) 167 (83.5) 507 (83.1)
NSAID 51 (24.8) 23 (11.3) 36 (18.0) 110 (18.0)
Both 8 (3.9) 4 (2.0) 3 (1.5) 15 (2.5)
Other or missing 4 (1.9) 4 (2.0) 0 8 (1.3)
Allopurinol dose at baseline (mg/day)
Mean (SD) 308.7 (69.29) 313.5 (78.33) 314.8 (77.62) 312.3 (75.08)
Min, max 200, 600 200, 900 200, 900 200, 900
ALLO, allopurinol; BMI, body mass index; CV, cardiovascular; eCrCl, estimated creatinine clearance; NSAID, non-steroidal anti-inflammatory drug; sUA, serum uric acid.
Figure 3 Proportions of patients achieving sUA target of <6.0 mg/dL (<357 mmol/L), <5.0 mg/dL (<297 mmol/L) and <4.0 mg/dL (<238 mmol/L),
by months 6 and 12 (ITT population) are shown. Primary end point: proportion of patients achieving sUA target of <6.0 mg/dL (<357 mmol/L) by
month 6. *p<0.0001. Note: Subjects missing sUA results were treated as non-responders. All comparisons used a two-sided Cochran-Mantel-
Haenszel test stratified by day −7 renal function and tophus status during screening (randomised stratification factor values), with non-responder
imputation and adjustment for multiple comparisons for the primary end point (Bonferroni correction). ALLO, allopurinol; ITT, intention to treat;
LESU, lesinurad; sUA, serum uric acid.
6 Bardin T, et al. Ann Rheum Dis 2016;0:1–10. doi:10.1136/annrheumdis-2016-209213
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7. the lesinurad 400 mg+allopurinol group. Non-MACE CV end
points were reported in five patients (five events), two patients
(two events) and no patients, respectively.
Other clinical laboratory tests and vital signs
Clinical laboratory results (excluding renal laboratory results,
reported above) and urinalysis were comparable between treat-
ment groups. Elevations in creatine kinase >5× upper limit of
normal were in 5.3%, 2.0% and 3.0% of allopurinol-alone, lesi-
nurad 200 mg+allopurinol and lesinurad 400 mg+allopurinol
groups, respectively. There were no notable changes in vital signs.
DISCUSSION
Allopurinol at the 300 mg dose is frequently unable to achieve
target sUA levels.5–8
Guidelines recommend increasing the allo-
purinol dose above 300 mg/day to attain target sUA, but this
happens rarely in practice, in part due to physician’s concerns
over safety of doses >300 mg.4 6 25–29
Other management
options include switching from allopurinol to febuxostat, or
adding a uricosuric to allopurinol, based on evidence from
earlier, small trials.30–32
CLEAR 2 and the similarly designed
CLEAR 115
were the initial large studies to validate a combin-
ation approach using a URAT1 inhibitor that inhibits uric acid
reabsorption (ie, lesinurad) with allopurinol.
In CLEAR 2, lesinurad at both doses (200 or 400 mg) com-
bined with continued allopurinol significantly increased the pro-
portions of patients achieving sUA target of <6.0 mg/dL
(<357 mmol/L) by month 6 (p<0.0001), with more than twice
as many patients reaching goal versus allopurinol-alone therapy.
Onset of sUA reduction in the lesinurad groups was rapid, with
significant differences from allopurinol-alone group by first
assessment at month 1. The significant increase in proportions
of patients who achieved sUA target in both lesinurad+allopur-
inol groups versus allopurinol-alone group was sustained over
the 12-month study. Consistent response rates were observed,
irrespective of renal function or thiazide diuretic use.
There were no statistically significant differences favouring
lesinurad treatment in the rates of gout flare requiring treatment
or complete resolution of tophi, which occurred at low inci-
dences at baseline and during study. In relation to these key
secondary end points, treatment may be required for more than
12 months for the full effects to be observed.33
Lesinurad was generally well tolerated, particularly at the
200 mg dose, where the TEAE and serious TEAE profiles were
comparable with the allopurinol-alone group. Higher TEAE
incidences were seen in the lesinurad 400 mg+allopurinol
group. Renal-related TEAEs occurred at similar incidences in
the lesinurad 200 mg+allopurinol and allopurinol-alone groups,
with a higher incidence in the lesinurad 400 mg+allopurinol
than lesinurad 200 mg+allopurinol group; the lesinurad
400 mg+allopurinol group also showed a higher incidence of
sCr elevation. The majority of sCr elevations resolved by the
next assessment and in most cases without interruption in study
medication. Mean renal function did not differ between the
treatment groups both before and after treatment. The mechan-
ism of sCr elevation associated with lesinurad may be via
increased excretion of urinary uric acid, which has the potential
to induce uric acid microcrystallisation in the renal tubules.
Urine protein-to-creatinine ratio and urinalyses did not change
during the study, suggesting that sCr elevation was not asso-
ciated with renal parenchymal sequelae. Patients with unre-
solved sCr elevations showed no defining characteristics
compared with those whose sCr elevation resolved.
Other therapies which inhibit URAT1 have been associated
with development of kidney stones.34 35
The lack of increase in
kidney stone numbers during lesinurad therapy is potentially
because of concomitant allopurinol use, which reduces uric acid
production.36 37
The rate of nephrolithiasis may also have been
influenced by timing of lesinurad administration, as once-daily
dosing in the morning increases urinary uric acid at a time when
urine volume and urine pH are highest and the potential for
uric acid precipitation is lowest.38 39
Prescribing information for the approved dose of lesinurad
200 mg recommends assessment of renal function prior to initi-
ation of therapy and periodically thereafter, particularly in
patients whose CrCl is 30–<45 mL/min, with discontinuation
recommended if CrCl is persistently <30 mL/min (ie, severe
renal impairment). Lesinurad is also contraindicated in subjects
with end-stage renal disease, kidney transplant recipients or
patients on dialysis.
Figure 4 Graph showing the mean
(SE) sUA levels by visit (observed
cases, intent-to-treat population).
Mean change from baseline for each
active treatment group was compared
with the ALLO-alone group using
analysis of covariance, with p<0.001
at each time point. ALLO, allopurinol;
LESU, lesinurad; sUA, serum uric acid.
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8. CV comorbidities and risk factors were present in approxi-
mately 80% of patients, reflecting the high rates of CV disease
in patients with gout.40–42
The proportions of patients with
TEAEs classified as CV events during study were low and similar
in treatment groups. Incidences of MACE events—that is,
serious CV events including CV deaths, non-fatal MI and non-
fatal stroke—were similarly low. Three patients experienced
MACE in the study, all receiving lesinurad 400 mg. Low rates of
MACE events during gout treatment were also reported in the
open-label Long-term Allopurinol Safety Study Evaluating
Outcomes in Gout Patients (LASSO) study, which reported a
rate of 0.58% over 6 months for MACE during allopurinol
treatment (incidence rate 1.42/100 patient-years).6
Limitations of CLEAR 2 include the limited data on allopur-
inol doses >300 mg, the relatively low proportion of women
enrolled, low number of patients with evaluable tophi and the
relatively short-term follow-up period that limits the ability to
adequately study flares and tophi. Rates of gout flares and
tophus resolution over the longer term are being investigated in
an extension study (NCT01808131).
In conclusion, lesinurad (200 and 400 mg), a novel SURI, in
combination with allopurinol significantly increased the propor-
tion of patients achieving the target sUA of <6.0 mg/dL
(<357 mmol/L) by month 6 and other sUA end points compared
with allopurinol-alone therapy. There were no statistically
significant treatment-group differences favouring lesinurad for
rate of gout flares or complete tophus resolution. The combin-
ation therapy was generally well tolerated, particularly at the
200 mg lesinurad dose approved by the US Food and Drug
Administration and European Medicines Agency, except for
higher incidences of predominantly reversible sCr elevation
compared with allopurinol-alone therapy. There were no cases
of unresolved sCr elevation ≥1.5× in the lesinurad 200 mg
+allopurinol group, versus three unresolved cases in the
allopurinol-alone group and seven in the lesinurad 400 mg
Table 2 Overall summary of TEAEs (safety population)
Adverse event
category, n (%)
ALLO
alone
(n=206)
Lesinurad 200
mg+ALLO
(n=204)
Lesinurad 400
mg+ALLO
(n=200)
Any TEAE 146 (70.9) 152 (74.5) 161 (80.5)
Any TEAE with RCTC
toxicity grade 3 or 4
23 (11.2) 19 (9.3) 27 (13.5)
Any TEAE possibly related
to randomised study
medication
39 (18.9) 40 (19.6) 50 (25.0)
Any serious TEAE 8 (3.9) 9 (4.4) 19 (9.5)
Any fatal TEAE 0 0 2 (1.0)
Any TEAE leading to
randomised study
medication discontinuation
11 (5.3) 7 (3.4) 19 (9.5)
Any TEAE leading to study
withdrawal
7 (3.4) 4 (2.0) 12 (6.0)
Individual serious TEAEs,
n (%)
Infections and infestations
Pneumonia 0 2 (1.0) 0
Bronchopneumonia 0 0 1 (0.5)
Cellulitis 0 0 1 (0.5)
Empyema 0 1 (0.5) 0
Pyelonephritis chronic 0 0 1 (0.5)
Sinobronchitis 0 1 (0.5) 0
Abscess limb 1 (0.5) 0 0
Appendicitis 1 (0.5) 0 0
Diverticulitis 1 (0.5) 0 0
Neoplasms benign, malignant and unspecified
Basal cell carcinoma 0 0 1 (0.5)
Gastric cancer 0 0 1 (0.5)*
Ovarian adenoma 0 1 (0.5) 0
Parathyroid tumour
benign
0 1 (0.5) 0
Prostate cancer 0 0 1 (0.5)
Pancreatic
neuroendocrine tumour
1 (0.5) 0 0
Metabolism and nutrition disorders
Gout flare 0 0 2 (1.0)
Psychiatric disorders
Depression 0 1 (0.5) 0
Dissociative disorder 0 0 1 (0.5)
Nervous system disorders
Subarachnoid
haemorrhage
1 (0.5) 0 0
Cardiac disorders
Myocardial infarction 0 0 3 (1.5%)
Atrial fibrillation 0 1 (0.5) 0
Coronary artery disease 0 0 1 (0.5)
Intracardiac thrombus 0 0 1 (0.5)
Vascular disorders
Hypertensive crisis 0 0 1 (0.5)
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema 0 0 1 (0.5)*
Gastrointestinal disorders
Duodenal ulcer
haemorrhage
1 (0.5) 0 1 (0.5)
Gastrointestinal
haemorrhage
0 1 (0.5) 0
Continued
Table 2 Continued
Adverse event
category, n (%)
ALLO
alone
(n=206)
Lesinurad 200
mg+ALLO
(n=204)
Lesinurad 400
mg+ALLO
(n=200)
Musculoskeletal and connective tissue disorders
Osteoarthritis 0 0 2 (1.0)
Arthralgia 0 1 (0.5) 0
Back pain 0 1 (0.5) 0
Flank pain 0 1 (0.5) 0
Intervertebral disc
degeneration
0 0 1 (0.5)
Renal and urinary disorders
Nephrolithiasis 0 0 2 (1.0)
Renal failure acute 1 (0.5) 0 1 (0.5)
Renal impairment 0 0 1 (0.5)
General disorders and administration site conditions
Adverse drug reaction 0 1 (0.5) 0
Non-cardiac chest pain 0 1 (0.5) 0
Injury, poisoning and procedural complications
Multiple drug overdose 0 1 (0.5) 0
Multiple injuries 0 1 (0.5) 0
Femur fracture 1 (0.5) 0 0
*Fatal serious TEAE.
ALLO, allopurinol; RCTC, Rheumatology Common Toxicity Criteria; TEAE,
treatment-emergent adverse event.
8 Bardin T, et al. Ann Rheum Dis 2016;0:1–10. doi:10.1136/annrheumdis-2016-209213
Clinical and epidemiological research
group.bmj.comon November 16, 2016 - Published byhttp://ard.bmj.com/Downloaded from
9. +allopurinol group. By using a dual mechanism approach to
reduce sUA, combination therapy with lesinurad and allopurinol
represents a treatment option for patients with gout inad-
equately controlled on allopurinol-alone therapy.
Author affiliations
1
Rhumatologie, Lariboisière Hospital, and Université Paris Diderot Sorbonne Cité,
Paris, France
2
Division of Rheumatology, Duke University School of Medicine, Durham, North
Carolina, USA
3
Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
4
Biometrics, Ardea Biosciences, Inc., San Diego, California, USA
5
Research & Development, Ardea Biosciences, Inc., San Diego, California, USA
6
Research & Development, AstraZeneca Pharmaceuticals, Gaithersburg, Maryland,
USA
7
Medical Affairs, Ardea Biosciences, Inc., San Diego, California, USA
8
Service de rhumatologie, Université de Lausanne, Lausanne, Switzerland
Acknowledgements Editorial support for this manuscript was provided by Bill
Wolvey of PAREXEL, which was funded by AstraZeneca.
Contributors TB, RTK, PPK and AS: Criterion 1: (1) substantial contributions to
study conception and design and/or (2) substantial contributions to analysis and
interpretation of data; criterion 2: drafting the article or revising it critically for
important intellectual content and criterion 3: final approval of the version of the
article to be published. JK, MF, NB, CS and SB: Criterion 1: (1) substantial
contributions to study conception and design and/or (2) substantial contributions to
acquisition of data and/or (3) substantial contributions to analysis and interpretation
of data; criterion 2: drafting the article or revising it critically for important
intellectual content and criterion 3: final approval of the version of the article to be
published. SA: criterion 1: (1) substantial contributions to acquisition of data and/or
(2) substantial contributions to analysis and interpretation of data; criterion 2:
drafting the article or revising it critically for important intellectual content and
criterion 3: final approval of the version of the article to be published.
Funding This clinical study was funded by Ardea Biosciences, a member of the
AstraZeneca group. The study sponsor had a role in the design and conduct of the
study; collection, management, analysis and interpretation of the data and review
and approval of the manuscript.
Competing interests TB: grant/research support from Ipsen, Menarini and
consultant for AstraZeneca, Ipsen, Menarini, Novartis, Savient, Sobi, Takeda and
Cymabay. RTK: consultant for AstraZeneca, Crealta Pharmaceuticals and Takeda.
PPK: research grant: AstraZeneca. JK (former employee), MF, NB, CS (former
employee) and SB: full-time employees of Ardea Biosciences, a member of the
AstraZeneca Group. SA: full-time employee of AstraZeneca Pharmaceuticals. AS:
consultant for Novartis, AstraZeneca, Menarini.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
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11. multinational CLEAR 2 study)
response to standard of care (the
study in patients with gout with inadequate
placebo-controlledrandomised, double-blind,
Lesinurad in combination with allopurinol: a
Alexander So
Fung, Nihar Bhakta, Scott Adler, Chris Storgard, Scott Baumgartner and
Thomas Bardin, Robert T Keenan, Puja P Khanna, Jeff Kopicko, Maple
published online November 7, 2016Ann Rheum Dis
13
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