Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: A 28‐week,phase III,randomized, double‐blind,parallel‐group trial

Objective

To compare the urate‐lowering efficacy and safety of febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function.

Methods

Subjects (n = 1,072) with hyperuricemia (serum urate level ≥8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to ≤2.0 mg/dl) renal function were randomized to receive once‐daily febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks.

Results

Significantly (P ≤ 0.05) higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with febuxostat than with allopurinol.

Conclusion

At all doses studied, febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.     

Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol

Objective

To compare the characteristics of female versus male gout patients and assess urate‐lowering efficacy and safety of febuxostat or allopurinol treatment in women with gout.

Methods

This was a retrospective analysis of 4,101 hyperuricemic (serum urate [sUA] level ≥8.0 mg/dl) gout subjects enrolled in 3 phase III comparative trials and randomized to receive placebo, febuxostat (40 mg, 80 mg, 120 mg, or 240 mg daily), or allopurinol (100 mg, 200 mg, or 300 mg daily, based on renal function). Baseline demographics and characteristics were summarized and compared between female and male subjects. Urate‐lowering efficacy, which was defined as the proportion of subjects with sUA levels <6.0 mg/dl at final visit, was assessed for all subjects and, among women, according to baseline renal function.

Results

Female gout subjects (n = 226) were older with significantly higher rates of obesity and metabolic and cardiovascular comorbidities than their male counterparts. The percentage of female subjects with sUA levels <6.0 mg/dl at final visit was 0% in the placebo group, 54.3%, 85.1%, 81.0%, and 100.0% in the febuxostat 40 mg, 80 mg, 120 mg, and 240 mg groups, respectively, and 45.9% in the allopurinol group. Similar patterns of urate‐lowering efficacy rates were observed when stratified by renal function. Among all the female subjects, febuxostat 80 mg was significantly more efficacious than allopurinol (P < 0.001). Rates of adverse events (AEs) were low. The most frequently reported AEs were upper respiratory tract infections, musculoskeletal/connective tissue disorders, and diarrhea.

Conclusion

These data suggest that febuxostat 80 mg may be more efficacious than commonly prescribed doses of allopurinol in female gout subjects with high rates of comorbidities.     

Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: A randomized,double‐blind,placebo‐controlled trial

Objective

A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 μg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double‐blind, placebo‐controlled clinical trial to compare placebo with 10 μg/kg/day and 25 μg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate‐to‐severe SSc.

Methods

Men and women ages 18–70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 μg/kg/day or 25 μg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28.

Results

The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo.

Conclusion

Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

     

Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: Results of a fifty‐two–week,randomized, controlled study

Objective

To assess the efficacy, safety, and tolerability of etoricoxib, a cyclooxygenase 2 (COX‐2) selective inhibitor, administered continuously over 52 weeks for the treatment of ankylosing spondylitis (AS).

Methods

This 2‐part, multicenter, double‐blind, parallel‐group, 52‐week study evaluated 2 doses of etoricoxib (90 and 120 mg) compared with naproxen at 1,000 mg. A 6‐week, active‐comparator– and placebo‐controlled period (part I) was followed by a 46‐week active‐comparator–controlled period (part II). The primary outcome measures (on 100‐mm visual analog scales) were patient's assessment of spine pain, patient's global assessment of disease activity, and the Bath Ankylosing Spondylitis Functional Index.

Results

Of the 387 patients randomized to receive treatment, 301 (77.8%) completed part I and 284 (75.9%) completed part II. Compared with placebo over 6 weeks, those receiving 90 mg etoricoxib, 120 mg etoricoxib, and naproxen demonstrated significantly (P < 0.001) greater improvement in all primary end points; treatment effects (expressed as the difference in least squares mean change versus placebo) were 21–29 mm for spine pain, 18–25 mm for disease activity, and 11–15 mm for function. Compared with patients receiving naproxen, significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks, in each individual etoricoxib treatment group over 6 weeks, and in the combined etoricoxib group over 1 year (all P < 0.05); results for secondary and exploratory end points were generally consistent with those from the primary analysis. Among all groups, there were no significant differences in the incidence of overall clinical, drug‐related, or serious adverse experiences (AEs) and discontinuations due to AEs. Safety observations during part II were generally consistent with those in part I.

Conclusion

Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks, and compared with naproxen over 1 year. These study results demonstrate that etoricoxib is generally safe, well‐tolerated, and efficacious for the treatment of AS.

     

Lack of a renal–protective effect of misoprostol in rheumatoid arthritis patients receiving cyclosporin a. results of a randomized,placebo–controlled trial

Objective. To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy. Methods. In this randomized, placebo–controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 μg/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks. Results. A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events. Conclusion. A renal–protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.     

Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: Results of a randomized,double‐blind,placebo‐controlled trial

Objective

To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia.

Methods

A double‐blind, placebo‐controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4–6 weeks of flexible dose escalation followed by 12 weeks of stable‐dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2‐measure composite response required achievement of ≥30% improvement from baseline in the pain score and a rating of “very much improved” or “much improved” on the Patient's Global Impression of Change (PGIC) scale. The 3‐measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF‐36) physical component summary (PCS) score.

Results

After 12 weeks of stable‐dose treatment, a significantly greater proportion of milnacipran‐treated patients compared with placebo‐treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2‐measure composite responder criteria (P < 0.001 in the baseline observation carried forward [BOCF] analysis) and 3‐measure composite responder criteria (P < 0.001 in the BOCF). Milnacipran‐treated patients also demonstrated significantly greater improvements from baseline on multiple secondary outcomes, including 24‐hour and weekly recall pain score, PGIC score, SF‐36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P < 0.001 versus placebo), and Multidimensional Fatigue Inventory total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo‐adjusted rate of 15.8%).

Conclusion

Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia.

     

Bixalomer in Hyperphosphatemic Patients With Chronic Kidney Disease Not on Dialysis: Phase 3 Randomized Trial

Currently, calcium‐ or metal‐containing phosphate binders are available to treat hyperphosphatemia in predialysis patients with chronic kidney disease. Bixalomer, a non‐calcium, metal‐free phosphate binder, has not been studied in these patients. We evaluated the efficacy and safety of bixalomer versus placebo for treatment of hyperphosphatemia in Japanese predialysis patients with chronic kidney disease. This multicenter, randomized, double‐blind, phase 3 trial, randomized eligible patients 1:1 to receive bixalomer or placebo for 12 weeks. Bixalomer was started at 1500 mg/day and adjusted up to 7500 mg/day depending on serum phosphorus concentrations. The primary endpoint was change in serum phosphorus concentration from baseline to end of treatment. After a 4‐week pre‐investigational period, 163 patients (bixalomer: N = 81; placebo: N = 82) were randomized. The adjusted mean change (95% confidence interval) from baseline to end of treatment in serum phosphorus was significantly greater with bixalomer (–0.78 [–0.98, –0.57] mg/dL) versus placebo (0.20 [–0.00, 0.41] mg/dL); mean difference: –0.98 (–1.27, –0.69), P < 0.001. At end of treatment, 57.5% of bixalomer‐treated patients achieved target serum phosphorus concentrations, mean serum intact parathyroid hormone and fibroblast growth factor‐23 decreased, and there were no significant changes in corrected serum calcium. The safety and tolerability of bixalomer was similar to placebo. The most common drug‐related adverse events were gastrointestinal (>24% patients per group). There was a significant increase in bicarbonate concentrations with bixalomer versus placebo (P = 0.003). Bixalomer was superior to placebo for hyperphosphatemia in Japanese predialysis patients with chronic kidney disease and may constitute a new treatment option.     

Predictors of embolization during protected renal artery angioplasty and stenting: Role of antiplatelet therapy

Objective: The objective of this study was to identify the predictors of distal embolization (DE) during protected renal artery angioplasty and stenting. Background: DE may contribute to worsening renal function after renal artery stenting. The factors associated with DE, rates of platelet‐rich emboli, and treatments that may prevent DE during renal stenting have not been evaluated. Methods: The current study evaluated patients randomized to receive an embolic protection device (EPD) in the RESIST trial. Forty‐two patients were identified for inclusion in this study. These patients were further randomized to abcizimab (N = 22) or placebo (N = 20). Modification in Diet in Renal Disease glomerular filtration rate (GFR) was used as the primary measure of renal function. Creatinine was measured by a modified Jaffe reaction using the IDMS‐traceable assay. The primary endpoint was capture of platelet rich emboli in the angioguard basket. Results: DE occurred in 15/42 (35%) of the patients and platelet rich DE in 10 (24%) of the patients who received an EPD. Of the angiographic characteristics only lesion length was significantly higher in patients with DE (16 ± 7 mm vs. 10 ± 5 mm, P = 0.04). Preprocedural abciximab reduced DE from 42 to 8% (P = 0.02). The rate of platelet rich emboli was 50% with neither abciximab nor a thienopyridine, 36% with thienopyridine only, 15% abciximab only, and 0% in patients who received both a thienopyridine and abciximab. Only Abciximab use was associated with improved renal function at 1‐month, thienopyridine was not. Angiographic characteristics including percent stenosis, minimal luminal diameter (MLD), reference diameter, change in MLD, contrast volume, and procedure time were not predictors of DE during renal stenting. Conclusion: Capture of DE and specifically platelet DE are common during protected renal stenting using a filter‐type EPD. Abciximab use, and potentially combined thienopyridine and abciximab use, decreased the rate of platelet rich DE; however, only abciximab improved renal function at 1‐month. © 2010 Wiley‐Liss, Inc.     

Efficacy and safety of tabalumab plus standard of care in Japanese patients with active systemic lupus erythematosus: Subgroup analyses of the ILLUMINATE-1 study

Objective: To assess the efficacy and safety of tabalumab, an anti-B cell activating factor (BAFF) antibody, in combination with standard of care (SoC) therapy in Japanese patients with active systemic lupus erythematosus (SLE).

Methods: A subgroup analysis was conducted in Japanese patients (n?=?45) enrolled in ILLUMINATE-1, a phase III global trial in SLE patients (N?=?1164). Patients received SoC plus tabalumab or placebo, starting with a loading dose (240?mg) at week 0, followed by 120?mg every 4 weeks (120 Q4W, n?=?15), 120?mg every 2 weeks (120 Q2W, n?=?15), or placebo Q2W (n?=?15). The primary endpoint was proportion achieving SLE Responder Index-5 (SRI-5) improvement at week 52.

Results: A numerically greater SRI-5 response rate was achieved with 120 Q2W (46.7%; p?=?0.059 vs. placebo) compared with 120 Q4W (20.0%) and placebo Q2W (13.3%). The proportion of patients with severe SLE flare was lower for 120 Q2W (0%) and 120 Q4W (6.7%) than for placebo (26.7%). The rates of serious adverse events (AEs) and treatment-emergent AEs were similar across treatments.

Conclusion: In Japanese SLE patients, tabalumab 120 Q2W improved SRI-5 response rate and reduced the frequency of severe flares compared with placebo. Safety profiles were similar with tabalumab and placebo.     

Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: A randomized placebo‐controlled study

Objective

Patients with systemic lupus erythematosus (SLE), with or without end‐stage renal failure, are at increased risk of premature cardiovascular disease. Although statin therapy has been found to reduce cardiovascular risk in the general population, its effectiveness in kidney transplant recipients with SLE has not been examined. This study was undertaken to investigate the effect of fluvastatin on cardiac end points in a randomized controlled trial of renal transplant patients with SLE.

Methods

Patients with SLE were identified from among participants in the Assessment of Lescol in Renal Transplantation trial, a randomized, double‐blind, placebo‐controlled study of the effect of fluvastatin (40–80 mg/day) on cardiovascular outcomes in renal transplant recipients. Patients were randomized to either a group receiving fluvastatin or a placebo group for the duration of the 5–6‐year trial, and then invited to continue in a 2‐year open‐label extension during which all participants, regardless of original group, received fluvastatin. Patients were followed up for a total of 7–8 years for assessment of the primary end point of major cardiac events, comprising nonfatal myocardial infarction, cardiac death, and coronary intervention procedures.

Results

Fluvastatin reduced low‐density lipoprotein cholesterol levels by 29.2% (95% confidence interval [95% CI] 18.3–40%), from a mean ± SD of 4.0 ± 0.9 mmoles/liter to 2.8 ± 1.1 mmoles/liter, and total cholesterol by 19.6% (95% CI 11.7–27.5%), from 6.4 ± 0.9 mmoles/liter to 5.1 ± 1.1 mmoles/liter. Compared with placebo‐treated patients, patients randomized to receive fluvastatin exhibited a 73.4% reduction in the risk of major cardiac events (relative risk 26.6 [95% CI 5.9–119.4], P = 0.064).

Conclusion

Our results indicate that the effect of fluvastatin on cardiac events in renal transplant recipients with SLE is similar to that observed with statin therapy in the renal transplant population as a whole.

     

Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy

Aims

Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin‐to‐creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit.

Materials and Methods

SONAR is a randomized, double‐blind, placebo‐controlled trial with approximately 3500 participants who have stage 2–4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin‐angiotensin system inhibitor.

Results

After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non‐responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end‐stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05).

Conclusion

SONAR aims to determine whether atrasentan added to guideline‐recommended therapies safely reduces the risk of CKD progression and delays the onset of end‐stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial “surrogate” response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease.     

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ～6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.     

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency

Objective: To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) ≥30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end‐stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed. Methods: In a 54‐week, randomized, double‐blind, parallel‐group study, patients with baseline glycosylated haemoglobin A_1c (HbA_1c) values of 6.5–10% were allocated (2:1) to sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day. Results: Patients (N = 91) with a mean baseline HbA_1c value of 7.7% (range: 6.2–10.3%) were randomized to sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA_1c was ?0.6% (?0.8, ?0.4) in the sitagliptin group compared with ?0.2% (?0.4, 0.1) in the placebo group [between‐group difference (95% CI) = ?0.4% (?0.7, ?0.1)]. At 54 weeks, patients continuously treated with sitagliptin had a mean change (95% CI) from baseline in HbA_1c of ?0.7% (?0.9, ?0.4). The overall incidence of adverse experiences was generally similar between groups. Between‐group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54‐week study [5 of 65 patients (7.7%) in the sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug‐related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups. Conclusions: In this study, sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.     

Achieving glycaemic control without weight gain,hypoglycaemia, or gastrointestinal adverse events in type 2 diabetes in the SUSTAIN clinical trial programme

Aim

To evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects.

Materials and methods

Data from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug‐naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol‐specified composite endpoint was the proportion of participants achieving HbA1c <53 mmol/mol (7.0%) at end of treatment (30 or 56 weeks) without weight gain and with no severe or blood glucose (BG)‐confirmed symptomatic hypoglycaemia. A post hoc composite endpoint was the proportion of participants achieving the primary composite endpoint without moderate or severe GI adverse events (AEs).

Results

Across the SUSTAIN trials 1 to 5, 3918 participants with T2D were randomized to once‐weekly subcutaneous semaglutide 0.5 mg, 1.0 mg, or comparators (placebo, sitagliptin 100 mg, exenatide extended release 2.0 mg or insulin glargine). The proportion of participants achieving HbA1c <53 mmol/mol (7.0%) with no weight gain and no severe/BG‐confirmed symptomatic hypoglycaemia was 47% to 66% (semaglutide 0.5 mg) and 57% to 74% (semaglutide 1.0 mg) vs 7% to 19% (placebo) and 16% to 29% (active comparators; all P < .0001). More participants achieved the primary composite endpoint with no moderate or severe GI AEs with semaglutide vs comparators (all P < .0001).

Conclusion

Semaglutide helped more people with T2D achieve HbA1c targets than did comparators in the SUSTAIN 1 to 5 trials, while avoiding unwanted outcomes such as weight gain, hypoglycaemia and GI side effects.     

Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment

Aim: To evaluate the efficacy and safety of saxagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) and renal impairment. Methods: In this multicentre, randomized, parallel‐group, double‐blind, placebo‐controlled study, patients with glycated haemoglobin (HbA1c) 7–11% and creatinine clearance <50 ml/min were stratified by baseline renal impairment (moderate, severe or end‐stage on haemodialysis), and randomized (1 : 1) to saxagliptin 2.5 mg once daily or placebo for 12 weeks. Oral antihyperglycaemic drugs and insulin therapy present at enrolment were continued throughout the study. The absolute change in HbA1c from baseline to week 12 (primary efficacy end‐point) was analysed using an analysis of covariance model with last observation carried forward methodology. Results: A total of 170 patients were randomized and treated. The adjusted mean decrease from baseline to week 12 in HbA1c was statistically significantly greater in the saxagliptin group than in the placebo group; the difference between treatments was ?0.42% (95% confidence interval: ?0.71 to ?0.12%, p = 0.007). Adjusted mean HbA1c decreases from baseline to week 12 were numerically greater with saxagliptin than with placebo in the subgroups of patients with moderate (?0.64 vs. ?0.05%) and severe (?0.95 vs. ?0.50%) renal impairment. HbA1c reductions were similar between saxagliptin and placebo in the subgroup with end‐stage renal disease on haemodialysis (?0.84 vs. ?0.87%). Saxagliptin was generally well tolerated; incidences of adverse events and hypoglycaemic events were similar to placebo. Conclusions: Saxagliptin 2.5 mg once daily is a well‐tolerated treatment option for patients with inadequately controlled T2DM and renal impairment.     

Fast onset of effect of budesonide/formoterol versus salmeterol/fluticasone and salbutamol in patients with chronic obstructive pulmonary disease and reversible airway obstruction

Background and objectives: Data on the onset of action of COPD medications are lacking. This study compared the onset of bronchodilation following different inhaled therapies in patients with moderate‐to‐severe COPD and reversible airway obstruction. Methods: In this double‐blind, double‐dummy, crossover study, 90 patients (aged ≥40 years; FEV₁ 30–70% predicted) were randomized to a single dose (two inhalations) of budesonide/formoterol 160/4.5 μg, salmeterol/fluticasone 25/250 μg, salbutamol 100 μg or placebo (via pressurized metered‐dose inhalers) on four visits. The primary end‐point was change in FEV₁ 5 min after drug inhalation; secondary end‐points included inspiratory capacity (IC) and perception of onset of effect. Results: Budesonide/formoterol significantly improved FEV₁ at 5 min compared with placebo (P < 0.0001) and salmeterol/fluticasone (P = 0.0001). Significant differences were first observed at 3 min. Onset of effect was similar with budesonide/formoterol and salbutamol. Improvements in FEV₁ following active treatments were superior to placebo after 180 min (all P < 0.0001); both combinations were better than salbutamol at maintaining FEV₁ improvements (P ≤ 0.0001) at 180 min. Active treatments improved IC at 15 and 185 min compared with placebo (P < 0.0001). Maximal IC was greater with budesonide/formoterol than salmeterol/fluticasone (P = 0.0184) at 65 min. Patients reported a positive response to the perceptions of the onset of effect question shortly after receiving active treatments (median time to onset 5 min for active treatments vs 20 min for placebo), with no significant difference between active treatments. Conclusion: Budesonide/formoterol has an onset of bronchodilatory effect in patients with COPD and reversible airway obstruction that is faster than salmeterol/fluticasone and similar to salbutamol.     

A randomized placebo-controlled trial of adefovir dipivoxil in advanced HIV infection: the ADHOC trial

Objectives

To assess the efficacy and safety of adefovir dipivoxil (ADV) added to stable background antiretroviral therapy (ART) in HIV‐infected individuals with advanced HIV disease.

Methods

ADHOC was a randomized, double‐blind, placebo‐controlled, international multicentre trial. Three hundred and one individuals with CD4 cell counts < 100 cells/μL or < 200 cells/μL with nadir < 50 cells/μL were allocated to receive either 120 mg ADV (subsequently 60 mg) (n = 161) or matching placebo (n = 140) once daily.

Results

Over a median follow‐up of 76 weeks, 23 (14%) and 18 (13%) participants assigned ADV and placebo, respectively, developed a new AIDS event or died (hazard ratio = 1.23, 95% confidence interval 0.66–2.29, P= 0.51). There was a lower incidence of new or recurrent herpes events in the ADV group (P = 0.009). The mean increase in CD4 cell count from baseline to week 24 was 23.0 and 24.4 cells/µL in ADV and placebo groups, respectively (P = 0.89), and the mean decrease in RNA was 0.32 and 0.35 log₁₀ copies/mL at week 24 (P = 0.87) in a subset of participants. There was greater weight loss in the ADV group during the trial (P = 0.007). One hundred and twenty‐four participants (41%) had stable background ART in the 8 weeks prior to and the 24 weeks after randomization. There was no significant imbalance in background ART regimens between the two treatment groups. Ninety‐seven serious adverse events (SAEs) occurred, 65 and 32 in the ADV and placebo groups, respectively, with significantly shorter time to first SAE in the ADV group (P = 0.002). A total of 33 participants developed proximal renal tubular dysfunction during the trial, all but one in the ADV group.

Conclusions

Due to the early termination of recruitment, ADHOC was unable to assess the original objective of clinical disease progression. Adding ADV to background antiretroviral therapy in advanced HIV disease did not provide immunological or virological improvement compared with placebo. Furthermore, at the doses used in this trial, ADV was associated with a significantly higher incidence of SAEs.

     

Safety and efficacy of faldaprevir in combination with pegylated interferon α‐2b and ribavirin in Japanese patients with genotype‐1 chronic hepatitis C virus infection

Aim

We evaluated the safety and efficacy of the hepatitis C virus (HCV) NS3/4A A protease inhibitor faldaprevir plus pegylated interferon α‐2b and ribavirin (PegIFNα‐2b/RBV) in Japanese patients with HCV genotype‐1 infection.

Methods

Treatment‐naïve patients were randomized (1:1) to faldaprevir 120 mg q.d. for 12 or 24 weeks (response‐guided therapy [RGT], n = 44), or faldaprevir 240 mg q.d. for 12 weeks (n = 43), each combined with PegIFNα‐2b/RBV for 24 or 48 weeks (RGT). Response‐guided therapy was based on early treatment success (HCV RNA <25 IU/mL at week 4 and <25 IU/mL undetected at week 8). Treatment‐experienced patients received 240 mg q.d. for 24 weeks, plus PegIFNα‐2b/RBV RGT (24 or 48 weeks, prior relapsers, n = 29) or PegIFNα‐2b/RBV (48 weeks, 5 prior partial responders/breakthroughs, 10 prior null responders). The primary objective was safety; sustained virologic response 12 weeks post‐treatment (SVR12) was a secondary end‐point.

Results

All except one patient experienced drug‐related adverse events. Adverse events led to faldaprevir discontinuation in 1 (2%), 13 (20%), and 3 (6.8%) patients on faldaprevir 120 mg, faldaprevir 240 mg 12 weeks, and faldaprevir 240 mg 24 weeks, respectively. The SVR12 rates were: 86% with faldaprevir 120 mg and 74% with faldaprevir 240 mg among treatment‐naïve patients; and 86%, 60%, and 40% among prior relapsers, partial responders/breakthroughs, and null responders, respectively.

Conclusions

In treatment‐naïve Japanese patients, faldaprevir 120 mg q.d. plus PegIFNα‐2b/RBV was better tolerated than faldaprevir 240 mg q.d. plus PegIFNα‐2b/RBV, with at least comparable efficacy. In treatment‐experienced patients, most prior relapsers achieved SVR12 with 24 weeks of faldaprevir 240 mg q.d. plus PegIFNα‐2b/RBV. Clinicaltrials.gov NCT01579474.

     

Metformin reduces the rate of small intestinal glucose absorption in type 2 diabetes

In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon‐like peptide‐1 (GLP‐1) secretion. We evaluated the effects of metformin on serum 3‐O‐methylglucose (3‐OMG; a marker of glucose absorption) and plasma total GLP‐1 concentrations during a standardized intraduodenal infusion of glucose and 3‐OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double‐blind, randomized, crossover design (14 days’ washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3‐OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3‐OMG ( P < .001) and higher plasma total GLP‐1 ( P = .003) concentrations. The increment in plasma GLP‐1 after metformin vs placebo was related to the reduction in serum 3‐OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP‐1 secretion in type 2 diabetes.